Triazoloquinazoline and pyrazolotriazolopyrimidine derivatives, medicinal compositions, adenosine a3 receptor affinity agents, ocular tension lowering agents, preparations for preventing and treating glaucoma and method of lowering ocular tension

ABSTRACT

The present invention provides triazoloquinazoline and pyrazolotriazolopyrimidine derivatives represented by the following general formula (1):  
                 
 
     wherein R 1  and R 2  represent the same groups as those described in the description; and A represents a pyrazole or benzene ring which is optionally substituted with the groups described in the description. These derivatives exhibit an affinity to an adenosine A3 receptor and also have an intraocular-pressure reducing effect, and are useful for prevention or treatment of glaucoma.

TECHNICAL FIELD

[0001] The present invention relates to novel triazoloquinazoline andpyrazolotriazolopyrimidine derivatives which exhibit an affinity to anadenosine A3 receptor, a pharmaceutical composition containing thederivatives, an adenosine A3 receptor affinitive agent, anintraocular-pressure reducing agent, a pharmaceutical preparation forprevention and treatment of glaucoma, and an intraocular-pressurereducing method.

BACKGROUD ART

[0002] J. Heterocyclic Chem., 31, 1171 (1994) discloses that2-aryl-8-fluorobenzyl-1,2,4-triazolo[5,1-i]purine is useful as anadenosine A2 receptor antagonist.

[0003] Eur. J. Med. Chem., 28, 569 (1993) describes that apyrazolotriazolopyrimidine derivative exhibits an adenosine A2 receptorantagonist effect. Also J. Med. Chem., 34(1), 281 (1991) describes thata triazoloquinazoline derivative exhibits high affinity to abenzodiazepine receptor.

[0004] An object of the present invention is to provide a novel compoundhaving an affinity to an adenosine A3 receptor.

DISCLOSURE OF THE INVENTION

[0005] To achieve the object described above, the present inventionprovides triazoloquinazoline and pyrazolotriazolopyrimidine derivativesrepresented by the following general formula (1):

[0006] wherein R¹ represents a lower alkyl group, a phenyl group, alower alkoxycarbonyl lower alkyl group, or a carboxy lower alkyl group;R² represents a pyridyl group, a furyl group, a thienyl group, or aphenyl group which optionally has 1 to 3 groups selected from loweralkyl group, halogen atom, phenyl group, halogen-substituted lower alkylgroup, hydroxy group, lower alkoxy group, N,N-di lower alkylamino group,lower alkylthio group, lower alkanoyloxy group and nitro group as asubstituent; A represents a pyrazole ring which is optionallysubstituted with a group selected from lower alkyl group, phenyl loweralkyl group, lower alkoxycarbonyl lower alkyl group, carboxy lower alkylgroup and hydroxy lower alkyl group as a substituent, or a benzene ringwhich is optionally substituted with 1 to 2 groups selected from halogenatom, lower alkyl group, nitro group and lower alkoxy group as asubstituent; with the exception that A is a benzene ring, R² is apyridyl group or a phenyl group, and R¹ is a methyl group, an ethylgroup or a phenyl group.

[0007] These triazoloquinazoline and pyrazolotriazolopyrimidinederivatives of the present invention are novel compounds which havenever been described in reference documents.

[0008] The pyrazolotriazolopyrimidine derivative in the presentinvention is represented by the following general formula (1-1):

[0009] wherein R¹ and R² are as defined above.

[0010] In the present invention, it is particularly preferable that R²is a phenyl group which optionally have one group selected from loweralkyl group, halogen atom, halogen-substituted lower alkyl group andhydroxy group as a substituent, or phenyl group which has 1 to 3 loweralkoxy groups.

[0011] In that case, A is preferably a pyrazole ring, or a benzene ringwhich is optionally substituted with one halogen atom as a substituent.More preferably, R¹ is an n-butyl group and R² is a phenyl group whichoptionally has one group selected from lower alkoxy group, lower alkylgroup, halogen atom and hydroxy group as a substituent.

[0012] Specifically, preferable compound is a compound selected fromcompound in which A is a pyrazole ring and R² is a phenyl group havingany one of lower alkoxy group, lower alkyl group or halogen atom as asubstituent, compound in which A is a benzene ring and R² is a phenylgroup having one group selected from lower alkoxy group, halogen atomand hydroxy group as a substituent, and compound in which A is a benzenering substituted with one halogen atom and R² is a phenyl group, and thecompound includes the following compounds:

[0013]5-n-butyl-2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,

[0014] 5-n-butyl-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline,

[0015] 5-n-butyl-2-(4-ethoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline,and

[0016] 5-n-butyl-9-chloro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline.

[0017] The compound of the present invention is more preferably acompound wherein R² is a phenyl group which has a lower alkyl group or ahalogen atom at the 4-position, and the compound include the followingcompounds:

[0018]5-n-butyl-2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,

[0019]5-n-butyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,

[0020]5-n-butyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,

[0021] 5-n-butyl-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline,

[0022] 5-n-butyl-2-(4-bromophenyl)-1,2,4-triazolo[1,5-c]quinazoline, and

[0023]5-n-butyl-2-(4-chlorophenyl)-9-chloro-1,2,4-triazolo[1,5-c]quinazoline.

[0024] The compound of the present invention is still more preferably5-n-butyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidineor 5-n-butyl-2-(4-bromophenyl)-1,2,4-triazolo[1,5-c]quinazoline, amongthe compounds described above.

[0025] It is expected that the compound of the present invention isapplied to antihypertensive agent, antiallergic agent, antiinflammatoryagent, remedy for ischemic heart disease, remedy for leukemia,antipruritic, expectorant, cough remedy, remedy for asthma, analgesic,intraocular-pressure reducing agent and pharmaceutical preparation forprevention or treatment of glaucoma as a compound capable of bindingwith an adenosine A3 receptor because of its excellent affinity to anadenosine A3 receptor.

[0026] Therefore, the present invention provides a pharmaceuticalcomposition comprising a compound selected from the triazoloquinazolineand pyrazolotriazolopyrimidine derivatives and a pharmaceuticallyacceptable carrier.

[0027] Also the present invention provides an adenosine A3 receptoraffinitive agent comprising a compound selected from thetriazoloquinazoline and pyrazolotriazolopyrimidine derivatives as anactive ingredient.

[0028] Furthermore, the present invention provides anintraocular-pressure reducing method, which comprises administering aneffective amount of a compound selected from the triazoloquinazoline andpyrazolotriazolopyrimidine derivatives to a patient having an enhancedintraocular pressure.

BEST MODE FOR CARRYING OUT THE INEVNTION

[0029] In the present invention, the lower alkyl group includes, forexample, straight-chain or branched lower alkyl groups having 1 to 6carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl,tert-butyl, pentyl, and hexyl.

[0030] The lower alkoxy group includes, for example, straight-chain orbranched lower alkoxy groups having 1 to 6 carbon atoms, such asmethoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0031] The halogen atom includes fluorine, chlorine, bromine, or iodine.The pyridyl group includes 2-pyridyl, 3-pyridyl or 4-pyridyl.

[0032] The furyl group includes 2-furyl or 3-furyl.

[0033] The thienyl group includes 2-thienyl or 3-thienyl.

[0034] The alkoxycarbonyl lower alkyl group includes C₁-C₆ lower alkylgroups substituted with a C₁-C₆ lower alkoxycarbonyl group, such asmethoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl,butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl,2-methoxycarbonylethyl, 1-methoxycarbonylethyl, 3-methoxycarbonylpropyl,4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, and6-methoxycarbonylhexyl.

[0035] The carboxy lower alkyl group includes C₁-C₆ lower alkyl groupssubstituted with a carboxy group, such as carboxymethyl, 2-carboxyethyl,1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, and6-carboxyhexyl.

[0036] The hydroxy lower alkyl group includes C₁-C₆ lower alkyl groupssubstituted with a hydroxy group, such as hydroxymethyl, 2-hydroxyethyl,1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and6-hydroxyhexyl.

[0037] The lower alkanoyloxy group includes lower alkanoyloxy groupswherein a C₁-C₆ straight-chain or branched lower alkyl group is bound tocarbonyl carbon, such as acetoxy, propionyloxy, butyryloxy,isobutyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy, and heptanoyloxy.

[0038] The phenyl which optionally has 1 to 3 groups selected from loweralkyl group, halogen atom, phenyl group, halogen-substituted lower alkylgroup, hydroxy group, lower alkoxy group, N,N-di lower alkylamino group,lower alkylthio group, lower alkanoyloxy group and nitro group as asubstituent includes, for example, phenyl groups which optionally have 1to 3 substituents selected from C₁-C₆ alkyl group, halogen atom, phenylgroup, halogen-substituted C₁-C₆ alkyl group, hydroxy group, C₁-C₆alkoxy group, N,N-di C₁-C₆ alkylamino group, C₁-C₆ alkylthio group,C₁-C₆ alkanoyloxy group and nitro group as a substituent, such as2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-t-butylphenyl,4-pentylphenyl, 4-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 3,4-diethylphenyl, 3,4-dipropylphenyl,3,4-dibutylphenyl, 3,4-dipentylphenyl, 3,4-dihexylphenyl,3,4,5-trimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl,2,3,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4,5-trimethylphenyl,3,4,5-triethylphenyl, 3,4,5-tripropylphenyl, 3,4,5-tributylphenyl,3,4,5-tripentylphenyl, 3,4,5-trihexylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl,3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl,2,6-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl,2,4-diiodophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl,4-biphenylyl, 3-biphenylyl, 2-biphenylyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl,4-nonafluorobutylphenyl, 4-undecafluoropentylphenyl,4-tridecafluorohexylphenyl, 3-trifluoromethylphenyl,2-trifluoromethylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl,2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl,3,5-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2,3,4-trihydroxyphenyl,2,3,5-trihydroxyphenyl, 2,3,6-trihydroxyphenyl, 2,4,6-trihydroxyphenyl,2,4,5-trihydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl,4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-diethoxyphenyl,3,4-dipropoxyphenyl, 3,4-dibutoxyphenyl, 3,4-dipentyloxyphenyl,3,4-dihexyloxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl,2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl,2,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 3,4,5-tripropoxyphenyl,3,4,5-tributoxyphenyl, 3,4,5-tripentyloxyphenyl,3,4,5-trihexyloxyphenyl, 4-(N,N-dimethylamino)phenyl,4-(N,N-diethylamino)phenyl, 4-(N,N-dipropylamino)phenyl,4-(N,N-dibutylamino)phenyl, 4-(N,N-dipentylamino)phenyl,4-(N,N-dihexylamino)phenyl, 3-(N,N-dimethylamino)phenyl,2-(N,N-dimethylamino)phenyl, 4-methylthiophenyl, 4-ethylthiophenyl,4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl,4-hexylthiophenyl, 3-methylthiophenyl, 2-methylthiophenyl,2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-dinitrophenyl,2,4-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl,3,4-dinitrophenyl, 3,5-dinitrophenyl, 3,4,5-trinitrophenyl,2,3,4-trinitrophenyl, 2,3,5-trinitrophenyl, 2,3,6-trinitrophenyl,2,4,6-trinitrophenyl, 2,4,5-trinitrophenyl, 4-methoxy-3-methylphenyl,4-methoxy-2-methylphenyl, 3-methoxy-2-methylphenyl,4-methoxy-3,5-dimethylphenyl, 4-hydroxy-3-methylphenyl,4-hydroxy-2-methylphenyl, 3-hydroxy-2-methylphenyl,2-hydroxy-4-methylphenyl, 2-hydroxy-4-methoxyphenyl,4-hydroxy-3,5-dimethylphenyl, 3,5-di-t-butyl-4-hydroxyphenyl,4-hydroxy-3,5-dimethoxyphenyl, 3,5-dihydroxy-4-methoxyphenyl,4-chloro-3-methoxyphenyl, 3-chloro-4-methoxyphenyl,4-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxyphenyl,4-chloro-3-methylphenyl, 3-chloro-4-methylphenyl,4-chloro-3,5-dimethoxyphenyl, 4-chloro-3,5-dimethylphenyl,4-acetoxyphenyl, 4-propionyloxyphenyl, 4-butyryloxyphenyl,4-isobutyryloxyphenyl, 4-valeryloxyphenyl, 4-pivaloyloxyphenyl,4-hexanoyloxyphenyl, 4-heptanoyloxyphenyl, 3,5-diacetoxyphenyl,3,4-diacetoxyphenyl, 3,4,5-triacetoxyphenyl, and 2,4,6-triacetoxyphenyl,in addition to the phenyl group.

[0039] In case the benzene ring itself is represented as a phenylenegroup, the benzene ring which is optionally substituted with 1 to 2groups selected from halogen atom, lower alkyl group, nitro group andlower alkoxy group as a substituent includes, for example, benzene ringswhich are optionally substituted with 1 to 2 groups selected fromhalogen atom, C₁-C₆ alkyl group, nitro group and C₁-C₆ alkoxy group as asubstituent, such as 2-chloro-1,6-phenylene, 3-chloro-1,6-phenylene,4-chloro-1,6-phenylene, 2-bromo-1,6-phenylene, 3-bromo-1,6-phenylene,2-iodo-1,6-phenylene, 3-iodo-1,6-phenylene, 2-fluoro-1,6-phenylene,3-fluoro-1,6-phenylene, 4-fluoro-1,6-phenylene,2,4-dichloro-1,6-phenylene, 2,3-dichloro-1,6-phenylene,3,4-dichloro-1,6-phenylene, 2,5-dichloro-1,6-phenylene,2,4-difluoro-1,6-phenylene, 2,4-dibromo-1,6-phenylene,2,4-diiodo-1,6-phenylene, 2-methyl-1,6-phenylene,3-methyl-1,6-phenylene, 4-methyl-1,6-phenylene, 2-ethyl-1,6-phenylene,2-propyl-1,6-phenylene, 2-isopropyl-1,6-phenylene,2-butyl-1,6-phenylene, 2-t-butyl-1,6-phenylene, 2-pentyl-1,6-phenylene,2-hexyl-1,6-phenylene, 2,3-dimethyl-1,6-phenylene,2,4-dimethyl-1,6-phenylene, 2,5-dimethyl-1,6-phenylene,3,4-dimethyl-1,6-phenylene, 3,4-diethyl-1,6-phenylene,3,4-dipropyl-1,6-phenylene, 3,4-dibutyl-1,6-phenylene,3,4-dipentyl-1,6-phenylene, 3,4-dihexyl-1,6-phenylene,2-methoxy-1,6-phenylene, 3-methoxy-1,6-phenylene,4-methoxy-1,6-phenylene, 3-ethoxy-1,6-phenylene,3-propoxy-1,6-phenylene, 3-butoxy-1,6-phenylene, 3-pentyl-1,6-phenylene,3-hexyl-1,6-phenylene, 2,3-dimethoxy-1,6-phenylene,2,4-dimethoxy-1,6-phenylene, 2,5-dimethoxy-1,6-phenylene,3,4-dimethoxy-1,6-phenylene, 3,4-diethoxy-1,6-phenylene,3,4-dipropoxy-1,6-phenylene, 3,4-dibutoxy-1,6-phenylene,3,4-dipentyloxy-1,6-phenylene, 3,4-dihexyloxy-1,6-phenylene,4-methoxy-3-methyl-1,6-phenylene, 4-methoxy-2-methyl-1,6-phenylene,3-methoxy-2-methyl-1,6-phenylene, 4-chloro-3-methyl-1,6-phenylene,4-chloro-2-methyl-1,6-phenylene, 3-chloro-2-methyl-1,6-phenylene,2-chloro-4-methyl-1,6-phenylene, 2-chloro-4-methoxy-1,6-phenylene,4-chloro-3-methyl-1,6-phenylene, 4-chloro-3-di-t-butyl-1,6-phenylene,4-chloro-3-methoxy-1,6-phenylene, 3-chloro-4-methoxy-1,6-phenylene,4-chloro-3-methoxy-1,6-phenylene, 4-butoxy-3-chloro-1,6-phenylene,2-chloro-5-methoxy-1,6-phenylene, 2-nitro-1,6-phenylene,3-nitro-1,6-phenylene, 4-nitro-1,6-phenylene, and 5-nitro-1,6-phenylene,in addition to the 1,6-phenylene group.

[0040] The pyrazole ring which is optionally substituted with a groupselected from lower alkyl group, phenyl lower alkyl group, loweralkoxycarbonyl lower alkyl group, carboxy lower alkyl group and hydroxylower alkyl group as a substituent include, for example, pyrazole ringswherein hydrogen bound to either of nitrogen atom is substituted withthe respective groups described above, in addition to thenon-substituted pyrazole ring.

[0041] The compound (1a) of the present invention can be prepared by thefollowing reaction scheme-1.

[0042] wherein R² is as defined above; R^(1a) represents a lower alkylgroup or a phenyl group; A1 represents a non-substituted pyrazole ring,or a benzene ring which is optionally substituted with 1 to 2 groupsselected from halogen atom, lower alkyl group, nitro group and loweralkoxy group as a substituent; and Z represents a lower alkyl group.

[0043] First, a compound represented by the formula (2) is reacted withan orthoester derivative represented by the formula (3) to obtain animino ester represented by the formula (4). This reaction is carried outby adding the orthoester derivative (3) in an equimolar amount or morerelative to the amount of the compound (2) and heating at a temperaturewithin a range from room temperature to reflux temperature for about 10minutes to 24 hours in the absence of a solvent, or in an inert solvent.As the inert solvent, for example, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methanol,diphenyl ether, xylene, and diethylene glycol dimethyl ether can beused.

[0044] The resulting imino ester derivative (4) is reacted with an acylhydrazine derivative (5), after the imino ester derivative is purifiedaccording to a conventional method or not, to obtain the compounds (1a)of the present invention.

[0045] This reaction is carried out by adding the acyl hydrazinederivative (5) in an equimolar amount or more relative to the amount ofthe imino ester derivative (4) in an inert solvent and heating at atemperature within a range from 50° C. to reflux temperature for about 1to 50 hours. The inert solvent includes the same solvents as thosedescribed above.

[0046] The above-described two-stage reaction can also be carried outsimultaneously in the same reaction vessel. For example, the reactioncan be carried out by adding the acyl hydrazine derivative (5) in thereaction mixture of the compound (2) and the orthoester derivative (3)and heating in the same manner. In this case, a trace amount of an acidcatalyst such as p-toluenesulfonic acid, camphorsulfonic acid, sulfuricacid or trifluoroacetic acid is preferably added in the reaction system.

[0047] The compound (1a′) of the present invention is converted into thecompound (1b) of the present invention by the hydrolysis reaction, thereaction with an acid chloride (7) or the cyclization reaction, as shownin the following reaction scheme-2.

[0048] wherein R² and A1 are as defined above; R^(1a′) represents alower alkyl group; R^(1b) represents a lower alkyl group, a phenyl groupor a lower alkoxycarbonyl lower alkyl group, R^(2b) represents a pyridylgroup, a furyl group, a thienyl group, or a phenyl group whichoptionally have 1 to 3 groups selected from lower alkyl group, halogenatom, phenyl group, halogen-substituted lower alkyl group, hydroxygroup, lower alkoxy group, N,N-di lower alkylamino group, loweralkylthio group and nitro group as a substituent; and R^(2c) representsa pyridyl group, a furyl group, a thienyl group, or a phenyl group whichoptionally have 1 to 3 groups selected from lower alkyl group, halogenatom, phenyl group, halogen-substituted lower alkyl group, lower alkoxygroup, N,N-di lower alkylamino group, lower alkylthio group, loweralkanoyloxy group and nitro group as a substituent.

[0049] First, the compound (1a′) is converted into an amine compound (6)by refluxing in an aqueous solution of mineral acid such as hydrochloricacid or sulfuric acid for 5 minutes to 50 hours.

[0050] Then, the amine compound (6) is acylated. This acylation can becarried out by reacting the amine compound (6) with the acid chloride(7) in an amine-based inert solvent such as pyridine, lutidine,triethylamine, or 4-(N,N-dimethylamino)pyridine. In this reaction, theacid chloride (7) is used in an equimolar amount or more and thereaction is completed within about 10 minutes to 3 hours at atemperature within a range from 0° C. to reflux temperature. Since acompound substituted with a plurality of acyl groups may be includedsometime in the acylation reaction, the inclusion can optionally beconverted into a desired monoacyl compound (8) by refluxing the product,together with a catalytic amount of an alkaline such as anhydrouspotassium carbonate or anhydrous sodium carbonate, in an inert solventsuch as methanol or ethanol for about 10 minutes to 2 hours.

[0051] Subsequently, the monoacyl compound (8) thus obtained isconverted into a compound (1b) of the present invention by thecyclization reaction. The cyclization reaction is carried out byreacting the monoacyl compound (8) with a halogenated trialkylsilane inan inert solvent in the presence of a base.

[0052] As the inert solvent, for example, there can be used aromatic andaliphatic hydrocarbons such as benzene, toluene, xylene, and petroleumether; ethers such as diethyl ether and tetrahydrofuran; halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,and 1,2-dichloroethane; and aliphatic nitrites such as acetonitrile. Asthe base, for example, tertiary amine such as triethylamine,diisopropylamine, N,N-diethylaniline, N-methyl morpholine, pyridine, or4-(N,N-dimethylamino)pyridine can be preferably used. As the halogenatedtrialkylsilane, for example, chlorotrialkylsilane such aschlorotrimethylsilane, chlorotriethylsilane, chloroethyldimethylsilane,chlorodimethylpropylsilane, chlorobutyldimethylsilane,chlorotripropylsilane, tributylchlorosilane, orchloroethylmethylpropylsilane can be preferably used.

[0053] The amount of the halogenated trialkylsilane and base to be usedis not specifically limited, but is generally controlled to an equalequivalent weight or more, and preferably from 3- to 20-fold equivalentweight relative to the amount of the monoacyl compound (8). Thecyclization reaction is usually completed within about 05 to 100 hoursat a temperature within a range from 0 to 100° C.

[0054] Among the starting materials (1a′) in the reaction scheme-2, thecyclization reaction simultaneously proceeds when using the acidchloride (7) in the amount of 3-fold equivalent weight relative to theamount of a compound wherein A1 is a benzene ring which is optionallysubstituted with 1 to 2 groups selected from halogen atom, lower alkylgroup, nitro group and lower alkoxy group as a substituent in theacylation reaction after hydrolysis. Therefore, it becomes unnecessaryto carry out the cyclization reaction in that case.

[0055] The compound (1c) of the present invention can be converted intocompounds (1d-1) and (1d-2) wherein a substituent is introduced into thepyrazole ring by treating with a halide (9), as shown in the followingreaction scheme-3.

[0056] wherein R^(1b) is as defined above; R^(2a) represents a pyridylgroup, a furyl group, a thienyl group, or a phenyl group whichoptionally has 1 to 3 groups selected from lower alkyl group, halogenatom, phenyl group, halogen-substituted lower alkyl group, lower alkoxygroup, N,N-di lower alkylamino group, lower alkylthio group, loweralkanoyloxy group and nitro group as a substituent; R³ represents alower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyllower alkyl group, or a hydroxy lower alkyl group, R^(3a) represents alower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyllower alkyl group, or a trimethylsilyloxy-lower alkyl group; and Xrepresents a halogen atom.

[0057] The conversion is carried out by reacting with an equalequivalent weight or more of a halide (9) in an inert solvent such asDMF, DMA, or DMSO in the presence of an equal equivalent weight or moreof an alkali such as anhydrous potassium carbonate or anhydrous sodiumcarbonate at a temperature within a range from 0° C. to room temperaturefor 2 to 50 hours.

[0058] When using, as the halide (9), a compound wherein R^(3a) is atrimethylsilyloxy-lower alkyl group, contact of the compound with waterin a post treatment causes elimination of the trimethylsilyl group, andthus the trimethylsilyloxy-lower alkyl group is converted into thecorresponding hydroxy lower alkyl group.

[0059] The compound (1e) of the present invention can be converted intoa compound (if) by hydrolysis, as shown in the reacton scheme-4.

[0060] wherein R² and R^(2b) are as defined above; R^(1c) represents alower alkyl group, a phenyl group, or a lower alkoxycarbonyl lower alkylgroup; R^(1d) represents a lower alkyl group, a phenyl group, or acarboxy lower alkyl group; A2 represents a pyrazole ring which isoptionally substituted with a group selected from lower alkyl group,phenyl lower alkyl group, lower alkoxycarbonyl lower alkyl group andhydroxy lower alkyl group as a substituent, or a benzene ring which isoptionally substituted with 1 to 2 groups selected from halogen atom,lower alkyl group, nitro group and lower alkoxy group as a substituent;and A3 represents a pyrazole ring which is optionally substituted with agroup selected from lower alkyl group, phenyl lower alkyl group, carboxylower alkyl group and hydroxy lower alkyl group as a substituent, or abenzene ring which which is optionally substituted with 1 to 2 groupsselected from halogen atom, lower alkyl group, nitro group and loweralkoxy group as a substituent; provided that the substituents satisfy atleast one of (i) to (iii):

[0061] (i) R^(1c) is a lower alkoxycarbonyl lower alkyl group,

[0062] (ii) A2 is a pyrazole ring substituted with a loweralkoxycarbonyl lower alkyl group, and

[0063] (iii) R² is a phenyl group having a lower alkanoyloxy group.

[0064] The lower alkoxycarbonyl lower alkyl group and/or the loweralkanoyloxy group contained in the compound (1e) of the presentinvention are hydrolyzed by the hydrolysis reaction to form thecorresponding carboxy lower alkyl group and/or hydroxy group, therebyobtaining a compound (1f).

[0065] The reaction is carried out by treating with a solution of analkaline such as sodium hydroxide or potassium hydroxide in an inertsolvent such as methanol or ethanol. The amount of the alkaline ispreferably controlled to an equal equivalent weight or more and thereaction is usually completed within about 0.5 to 10 hours at atemperature within a range from about 0° C. to room temperature.

[0066] The desired object in each process of the above reaction schemes1 to 4 can be easily isolated and purified by a conventional separationmeans. The separation means includes adsorption chromatography,preparative thin-layer chromatography, recrystallization, solventextraction or the like.

[0067] When A is a pyrazole ring in the compounds (1) of the presentinvention prepared as described above, it is considered that thecompound includes the following four structural formulas as a tautomerand the tautomer can be represented by any of the structural formulas.

[0068] wherein R¹ and R² are as defined above.

[0069] The compounds (1) of the present invention can be formed intopharmaceutically acceptable acid addition salts, and these salts arealso included in the present invention. The acid capable of formingthese acid salts includes, for example, inorganic acids such ashydrochloric acid, hydrobromic acid, and sulfuric acid; and organicacids such as oxalic acid, fumaric acid, maleic acid, tartaric acid,citric acid, and p-toluenesulfonic acid. The acid addition salts can beformed by a conventional method.

[0070] Among the compounds of the present invention, thepyrazolotriazolopyrimidine derivative can be formed into alkaline metalsalts such as sodium salt and potassium salt; alkaline earth metal saltssuch as calcium salt and magnesium salt; and copper salts by aconventional method, and these salts can also be included in the presentinvention.

[0071] The compounds (1) of the present invention are used in the formof a general pharmaceutical preparation by using, together with asuitable non-toxic preparation carrier. The preparation carrier includediluents and excipients, such as fillers, extenders, binders,humectants, disintegrators, surfactants, and lubricants, which areusually used according to the service form of the preparation, and theseare appropriately selected and used according to the unit dosage form ofthe resulting preparation.

[0072] As the unit dosage form of the pharmaceutical preparation usingthe compound (1) of the present invention, various forms can be selectedaccording to the therapeutic purposes and typical examples thereofinclude tablets, pills, powders, liquid preparations, suspensions,emulsions, granules, capsules, suppositories, injections (e.g. liquidpreparations, suspensions, etc.), ointments, and opthalmic solutions.

[0073] In case of forming into the form of tablets, there can be used,as the preparation carrier, excipients such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid, and potassium phosphate; binders such as water,ethanol, propanol, simple syrup, glucose solution, starch solution,gelatin solution, carboxymethylcellulose, hydroxypropylcellulose,methylcellulose, and polyvinyl pyrrolidone; disintegrators such assodium carboxymethylcellulose, calcium carboxymethylcellulose, lowsubstituted hydroxypropylcellulose, dried starch, sodium alginate, agarpowder, laminaran powder, sodium hydrogencarbonate, and calciumcarbonate; surfactants such as polyoxyethylene sorbitan fatty acidesters, sodium lauryl sulfate, and monoglyceride stearate;disintegration inhibitors such as sucrose, stearin, cacao butter, andhydrogenated oil; absorption accelerators such as quaternary ammoniumbase and sodium lauryl sulfate; humectants such as glycerin and starch;adsorbents such as starch, lactose, kaolin, bentonite, and colloidalsilicic acid; and lubricants such as purified talc, stearate, powderedboric acid, and polyethylene glycol.

[0074] If necessary, tablets can be formed into tablets coated with acommon coating, for example, sugar-coated tablets, gelatin-coatedtablets, enteric coated tablets, film coating tablets, double layeredtablets, or mutilayer tablets.

[0075] In case of forming into the form of pills, there can be used, asthe preparation carrier, excipients such as glucose, lactose, starch,cacao butter, hardened vegetable oil, kaolin, and talc; binders such asgum arabic, powdered tragacanth, gelatin, and ethanol; anddisintegrators such as laminaran and agar.

[0076] In case of forming into the form of suppositories, there can beused, as the preparation carrier, polyethylene glycol, cacao butter,higher alcohol, esters of higher alcohol, gelatin, and semi-synthesizedglyceride.

[0077] Capsules are usually prepared by mixing the compound (1) of thepresent invention with various pharmaceutical preparations and filling ahard gelatin capsule or a soft gelatin capsule with the mixture.

[0078] In case of preparing as injections such as liquid preparations,emulsions or suspension, these are preferably sterilized and areisotonic with blood. In case of forming into the form of injections,there can be used, as the diluent, water, ethyl alcohol, macrogol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters. Inthis case, salt, glucose or glycerin may be contained in an enoughamount to prepare an isotonic solution and common solubilizers, bufferagents or soothing agents may also be added.

[0079] If necessary, the pharmaceutical preparation further containscolorants, preservatives, perfumes, flavors, sweeteners, or other drugs.

[0080] In case of forming into the form of ointments such as paste,cream, or gel, there can be used, as the diluent, white soft paraffin,paraffin, glycerin, cellulose derivative, polyethylene glycol, silicon,and bentonite.

[0081] The amount of the compound (1) of the present invention to beincorporated in the pharmaceutical preparation is not specificallylimited and appropriately selected from a wide range, but is preferablywithin a range from about 1 to 85% by weight based on the pharmaceuticalpreparation.

[0082] Eye drops are usually prepared by a conventional method usingsterilized distilled water as a base; buffer agents such as sodiumdihydrogenphosphate and sodium monohydrogenphosphate; isotonizing agentssuch as sodium chloride and concentrated glycerin; buffering agents suchas sodium phosphate and sodium acetate; surfactants such aspolyoxyethylene sorbitan monooleatae, polyoxy 40 stearate andpolyocyethylene hardened castor oil; solubilizers such as sodiumcarboxymethylcellulose, polyoxyethylene lauryl ether, polyoxyethyleneoleyl ether, polyethylene glycol monolaurate, and polyethylene glycolmonooleate; stabilizers such as sodium citrate and sodium edetate; andantiseptics such as benzatonium chloride, chlorobutanol, benzalkoniumchloride, and paraben. The pH is not specifically limited as far as itis within an ophthalmologically acceptable range, and is preferablywithin a range from 4 to 8.

[0083] The administration method of the pharmaceutical preparation isnot specifically limited, but is appropriately decided according to theform of preparations, age of patients, sex and other conditions, orconditions of diseases. For example, tablets, pills, liquidpreparations, suspensions, granules and capsules are orallyadministered, while injections are intravenously administered alone orin combination with a conventional replenisher such as glucose or aminoacid, or intramascularly, intracutaneously, subctaneously orintraperitoneally administered alone, if necessary. Furthermore,suppositories are intrarectally administered.

[0084] The dose of the pharmaceutical preparation varies depending onthe administration method, age of patients, sex and other conditions, orconditions of diseases, but a dairy dose of the compound (1) of thepresent invention is usually within a range from about 05 to 20 mg/kg,and preferably from about 1 to 10 mg/kg. The pharmaceutical preparationcan be administered 1 to 4 times per day.

INDUSTRIAL APPLICABILITY

[0085] It is expected that the compound of the present invention isapplied to antihypertensive agent, antiallergic agent, antiinflammatoryagent, remedy for ischemic heart disease, remedy for leukemia,antipruritic, expectorant, cough remedy, remedy for asthma, analgesic,intraocular-pressure reducing agent and pharmaceutical preparation forprevention or treatment of glaucoma as a compound capable of bindingwith an adenosine A3 receptor because of its excellent affinity to anadenosine A3 receptor.

EXAMPLES

[0086] The following Examples further illustrate the compounds of thepresent invention in detail.

Example 1

[0087] Preparation of5-methyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0088] 0.5 g of 3-amino-4-cyanopyrazole was suspended in 3 mL of DMF and0.61 g of trimethyl orthoacetate and 1 mg of p-toluenesulfonic acid(monohydrate), followed by stirring at 80° C. for 45 minutes. To thereaction solution, 0.69 g of N-benzoyl hydrazine was further added, andthen the mixture was refluxed for 14 hours. After the completion of thereaction, 10 mL of water was added when the reaction solution was cooledto about 100° C., followed by cooling to room temperature. The depositedcrystal was collected by filtration and then washed with hydrous ethanolto obtain 0.91 g of a desired compound as a crystal.

[0089] Melting point: >280° C.

Examples 2 to 86

[0090] In the same manner as in Example 1, the following compounds wereprepared.

[0091] (Example 2)5-ethyl-2-phenylpyrazole[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0092] Melting point: 274-275.5° C.

[0093] (Example 3)2-phenyl-5-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0094] Melting point: 247 to 248° C.

[0095] (Example 4)5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0096] Melting point: 214-215° C.

[0097] (Example 5)5-n-butyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0098] Melting point: 228 to 230° C.

[0099] (Example 6)5-n-butyl-2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0100] Melting point: 231-233° C.

[0101] (Example 7)2-(4-bromophenyl)-5-n-butylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0102] Melting point: 257-258° C.

[0103] (Example 8)5-n-butyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0104] Melting point: 242 to 243%

[0105] (Example 9)5-n-butyl-2-(4-t-butylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0106] Melting point: 197-199° C.

[0107] (Example 10)5-n-butyl-2-(4-trifluoromethylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0108] Melting point: 234-235° C.

[0109] (Example 11)2-(4-biphenylyl)-5-n-butylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0110] Melting point: 249-250° C.

[0111] (Example 12)5-n-butyl-2-(4-hydroxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0112] Melting point: >280° C.

[0113] (Example 13)5-n-butyl-2-(4-ethoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0114] Melting point: 204-205.5° C.

[0115] (Example 14)5-n-butyl-2-(4-propoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0116] Melting point: 191-192° C.

[0117] (Example 15)5-n-butyl-2-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0118] Melting point: 259-262° C.

[0119] (Example 16)5-n-butyl-2-[4-(N,N-dimethylamino)phenyl]pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0120] Melting point: >240% C (with decomposition)

[0121] (Example 17)5-n-butyl-2-(4-nitrophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0122] Melting point: 279-280.5° C.

[0123] (Example 18)5-n-butyl-2-(3-pyridyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0124] Melting point: 217-219° C.

[0125] (Example 19)5-n-butyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0126] Melting point: 253-254.5° C.

[0127] (Example 20)5-n-butyl-2-(2-thienyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0128] Melting point: 214-216° C.

[0129] (Example 21) 2-phenyl-5-propyl-1,2,4-triazolo[1,5-c]quinazoline

[0130] Melting point: 143-144° C.

[0131] (Example 22) 5-n-butyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0132] Melting point: 133-135° C.

[0133] (Example 23)5-n-butyl-2-(4-fluorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0134] Melting point: 167-169° C.

[0135] (Example 24)5-n-butyl-2-(2-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0136] Melting point: 104.5-105.55° C.

[0137] (Example 25)5-n-butyl-2-(3-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0138] Melting point: 129-131° C.

[0139] (Example 26)5-n-butyl-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0140] Melting point: 160-161° C. (Example 27)2-(4-bromophenyl)-5-n-butyl-1,2,4-triazolo[1,5-c]quinazoline

[0141] Melting point: 169-171° C. (Example 28)5-n-butyl-2-(4-methylphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0142] Melting point: 153-154° C.

[0143] (Example 29)5-n-butyl-2-(4-t-butylphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0144] Melting point: 106-108° C.

[0145] (Example 30)5-n-butyl-2-(4-trifluoromethylphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0146] Melting point: 157-159° C.

[0147] (Example 31)2-(4-biphenylyl)-5-n-butyl-1,2,4-triazolo[1,5-c]quinazoline

[0148] Melting point: 159-161° C.

[0149] (Example 32)5-n-butyl-2-(4-hydroxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0150] Melting point: 234-235.5° C.

[0151] (Example 33)5-n-butyl-2-(2-methoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0152] Melting point: 106.5-107.5° C.

[0153] (Example 34)5-n-butyl-2-(4-methoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0154] Melting point: 126-128° C.

[0155] (Example 35)5-n-butyl-2-(4-ethoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0156] Melting point: 149-150° C.

[0157] (Example 36)5-n-butyl-2-(4-propoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0158] Melting point: 128-129° C.

[0159] (Example 37)5-n-butyl-2-(3,4,5-trimethoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0160] Melting point: 130-133° C.

[0161] (Example 38)5-n-butyl-2-[4-(N,N-dimethylamino)phenyl]-1,2,4-triazolo[1,5-c]quinazoline

[0162] Melting point: 148.5-150° C.

[0163] (Example 39)5-n-butyl-2-(4-nitrophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0164] Melting point: 194-195° C.

[0165] (Example 40)5-n-butyl-2-(3-pyridyl)-1,2,4-triazolo[1,5-c]quinazoline

[0166] Melting point: 140-141.5° C.

[0167] (Example 41)5-n-butyl-2-(2-furyl)-1,2,4-triazolo[1,5-c]quinazoline

[0168] Melting point: 110-111.5° C.

[0169] (Example 42)5-n-butyl-2-(2-thienyl)-1,2,4-triazolo[1,5-c]quinazoline

[0170] Melting point: 147-149.5° C.

[0171] (Example 43)5-n-butyl-10-fluoro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0172] Melting point: 123-124° C.

[0173] (Example 44)5-n-butyl-10-chloro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0174] Melting point: 122-123° C.

[0175] (Example 45)5-n-butyl-9-chloro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0176] Melting point: 110-113° C.

[0177] (Example 46)5-n-butyl-8-chloro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0178] Melting point: 143-144° C.

[0179] (Example 47)9-bromo-5-n-butyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0180] Melting point: 129.5-132.5° C.

[0181] (Example 48)5-n-butyl-8,9-dimethoxy-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0182] Melting point: 150-152° C.

[0183] (Example 49)5-n-butyl-10-methyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0184] Melting point: 123-124° C.

[0185] (Example 50)5-n-butyl-8-methyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0186] Melting point: 136.5-138° C.

[0187] (Example 51)5-n-butyl-2-(2-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0188] Melting point: 206-207° C.

[0189] (Example 52)5-n-butyl-2-(3-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0190] Melting point: 240-242.5° C.

[0191] (Example 53)5-n-butyl-2-(2-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0192] Melting point: 157-160° C.

[0193] (Example 54)5-n-butyl-2-(3-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0194] (Example 55)5-n-butyl-2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0195] Melting point: 206-208° C.

[0196] (Example 56)5-n-butyl-2-(4-methylthiophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0197] Melting point: 204-205° C.

[0198] (Example 57)5-n-butyl-2-(3-methoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0199] Melting point: 118-119° C.

[0200] (Example 58)5-n-butyl-2-(4-methylthiophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0201] Melting point: 140.5-141.5° C.

[0202] (Example 59)2,5-diphenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0203] Melting point: 272.5-275° C.

[0204] (Example 60)2-(4-methylphenyl)-5-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0205] Melting point: 274-275° C.

[0206] (Example 61)5-n-butyl-2-(4-ethylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0207] Melting point: 208.5-210° C.

[0208] (Example 62)5-n-butyl-2-(4-n-propylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0209] Melting point: 207.5-209° C.

[0210] (Example 63)5-ethyl-2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0211] Melting point: 274-277° C.

[0212] (Example 64)2-(4-chlorophenyl)-5-ethylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0213] Melting point: >280° C.

[0214] (Example 65)5-ethyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0215] Melting point: >280° C.

[0216] (Example 66)2-(4-bromophenyl)-5-ethyl-1,2,4-triazolo[1,5-c]quinazoline

[0217] Melting point: 197-198° C.

[0218] (Example 67)5-ethyl-2-(4-fluorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0219] Melting point: 195-196° C.

[0220] (Example 68)2-(4-chlorophenyl)-5-ethyl-1,2,4-triazolo[1,5-c]quinazoline

[0221] Melting point: 197-198° C.

[0222] (Example 69)5-ethyl-2-(4-methylphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0223] Melting point: 147-148′ (Example 70)5-ethyl-2-(4-hydroxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0224] Melting point: >280° C.

[0225] (Example 71)5-ethyl-2-(4-methoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0226] Melting point: 167.5-168° C.

[0227] (Example 72)2-(4-ethoxyphenyl)-5-ethyl-1,2,4-triazolo[1,5-c]quinazoline

[0228] Melting point: 153-154° C.

[0229] (Example 73)9-chloro-2-phenyl-5-n-propyl-1,2,4-triazolo[1,5-c]quinazoline

[0230] Melting point: 140.5-141.5° C.

[0231] (Example 74)5-n-butyl-9-chloro-2-(4-fluorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0232] Melting point: 147.5-150° C.

[0233] (Example 75)5-n-butyl-9-chloro-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0234] Melting point: 138.5-140° C.

[0235] (Example 76)2-(4-bromophenyl)-5-n-butyl-9-chloro-1,2,4-triazolo[1,5-c]quinazoline

[0236] Melting point: 158-159.5° C.

[0237] (Example 77)5-n-butyl-9-chloro-2-(4-methylphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0238] Melting point: 141-143° C.

[0239] (Example 78)5-n-butyl-9-chloro-2-(4-methoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0240] Melting point: 124-125° C.

[0241] (Example 79)8-chloro-2-phenyl-5-n-propyl-1,2,4-triazolo[1,5-c]quinazoline

[0242] Melting point: 147-149° C.

[0243] (Example 80)5-n-butyl-8-chloro-2-(4-fluorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0244] Melting point: 185.5-186.5° C.

[0245] (Example 81)5-n-butyl-8-chloro-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0246] Melting point: 153.5-155° C. (Example 82)2-(4-bromophenyl)-5-n-butyl-8-chloro-1,2,4-triazolo[1,5-c]quinazoline

[0247] Melting point: 150-151° C.

[0248] (Example 83)5-n-butyl-8-chloro-2-(4-methylphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0249] Melting point: 134-134.5° C.

[0250] (Example 84)5-n-butyl-8-chloro-2-(4-methoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline

[0251] Melting point: 138.5-139.5° C.

[0252] (Example 85)5-n-butyl-9-nitro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0253] Melting point: 205.5-206° C.

[0254] (Example 86)9-chloro-2-(4-chlorophenyl)-5-ethyl-1,2,4-triazolo[1,5-c]quinazoline

[0255] Melting point: 213-214° C.

Example 87

[0256] Preparation of5-n-pentyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0257] 3 g of the compound(5-ethyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine)obtained in Example 2 was dissolved in a mixed solution of 6 ml ofconcentrated hydrochloric acid and 30 ml of ethanol, followed by heatingat reflux for 20 minutes. To the reaction solution, 60 ml of water wasadded and, after cooling to room temperature, the pH of the solution wasadjusted to 8 by adding 25% aqueous ammonia. The deposited crystal wascollected by filtration to obtain 2.2 g of3-(3-aminopyrazol-4-yl)-5-phenyl-1,2,4-triazole.

[0258] To a solution of 0.5 g of the crystal in 5 ml of pyridine, asolution of 0.89 g of hexanoyl chloride in 5 ml of dichloromethane wasadded dropwise at 0° C. and, after stirring at 0° C. for 10 minutes,then at room temperature for 30 minutes, the mixture was heated atreflux for 15 minutes. The reaction solution was cooled to roomtemperature and the deposited crystal was collected by filtration toobtain 0.45 g of3-[3-(N-hexanoylamino)pyrazol-4-yl]-5-phenyl-1,2,4-triazole (250-251°C.).

[0259] Subseqeuntly, 0.4 g of the crystal thus obtained was suspended in3 ml of acetonitrile and 1.0 ml of diisopropylethylamine and 0.78 ml ofchlorotrimethylsilane were added, followed by heating at reflux for 26hours. The reaction solution was cooled to room temperature, dilutedwith chloroform and then washed in turn with water and saturated saline.After the solvent was distilled off, the deposited crystal was washedwith heated 50% methanol to obtain 0.26 g of a desired compound as acrystal.

[0260] Melting point: 200-201° C.

Examples 88 to 107

[0261] In the same manner as in Example 87, the following compounds wereprepared.

[0262] (Example 88)5-n-hexyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0263] Melting point: 207-208° C. (Example 89) methyl4-[2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyrate

[0264] Melting point: 186-187° C.

[0265] (Example 90) methyl4-[2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyrate

[0266] Melting point: 187.5-188.5° C.

[0267] (Example 91) methyl4-[2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyrate

[0268] Melting point: 194.5-196.5° C.

[0269] (Example 92) methyl4-[2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyrate

[0270] Melting point: 196.5-197° C.

[0271] (Example 93) 5-n-pentyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0272] Melting point: 118-118.5° C.

[0273] (Example 94) 5-n-hexyl-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline

[0274] Melting point: 92-93° C.

[0275] (Example 95)2-(4-fluorophenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0276] Melting point: 133.5-134° C.

[0277] (Example 96) methyl4-(2-phenyl-1,2,4-triazolo[1,5-c]quinazolin-5-yl)butyrate

[0278] Melting point: 118.5-119.5° C.

[0279] (Example 97) methyl4-[2-(4-bromophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyrate

[0280] Melting point: 125-126° C.

[0281] (Example 98) methyl4-[2-(4-fluorophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyrate

[0282] Melting point: 167-168° C.

[0283] (Example 99) methyl4-[2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyrate

[0284] Melting point: 128-129° C.

[0285] (Example 100) methyl4-[2-(4-methylphenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyrate

[0286] Melting point: 120.5-121.5° C.

[0287] (Example 101)2-(4-methylphenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0288] Melting point: 129.5-131° C.

[0289] (Example 102)2-(4-bromophenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0290] Melting point: 133-134° C.

[0291] (Example 103)2-(4-chlorophenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0292] Melting point: 118-119.5° C.

[0293] (Example 104) methyl4-[9-chloro-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyrate

[0294] Melting point: 145-146.5° C.

[0295] (Example 105)2-(4-methoxyphenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0296] Melting point: 123-125° C.

[0297] (Example 106)2-(4-ethoxyphenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0298] Melting point: 116-117° C.

[0299] (Example 107)2-(4-hexanoyloxyphenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0300] Melting point: 805-82° C.

Examples 108 and 109

[0301] Preparation of5-n-butyl-2-(4-fluorophenyl)-7-methylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine(Example 108) and5-n-butyl-2-(4-fluorophenyl)-8-methylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine(Example 109)

[0302] 0.60 g of the compound(5-n-butyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine)obtained in Example and 0.32 g of anhydrous potassium carbonate weresuspended in 10 ml of DMF, followed by stirring at room temperature forone hours, then at 50° C. for 15 minutes. The mixed solution was cooledto 0° C. and 0.30 g of methyl iodide was added dropwise, followed bystirring at 0° C. for one hours, then at room temperature for 16 hours.To the reaction solution, iced water was added and the deposited crystalwas purified by silica gel column chromatography (as an eluent,chloroform was used and then a mixture of chloroform and methanol (50:1)was used) to obtain 0.36 g of a desired 7-methyl derivative (meltingpoint: 150.5-151.5° C.) from the first fraction and 0.19 g of a 8-methylderivative (melting point: 205.5-206.5° C.) from the second fraction.

Examples 110 to 146

[0303] In the same manner as in Examples 108 and 109, the followingcompounds were prepared.

[0304] (Example 110)5-n-butyl-7-methyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0305] Melting point: 172-173° C.

[0306] (Example 111)5-n-butyl-8-methyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0307] Melting point: 184-185° C.

[0308] (Example 112)5-n-butyl-2-phenyl-7-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0309] Melting point: 100.5-101.5° C.

[0310] (Example 113)5-n-butyl-2-phenyl-8-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0311] Melting point: 107-108° C.

[0312] (Example 114)5-n-butyl-7-ethyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0313] Melting point: 146-147° C.

[0314] (Example 115)5-n-butyl-8-ethyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0315] Melting point: 122.5-123° C.

[0316] (Example 116)7-benzyl-5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0317] Melting point: 108-109° C.

[0318] (Example 117)8-benzyl-5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0319] Melting point: 159-160° C.

[0320] (Example 118)2-(4-chlorophenyl)-5-n-butyl-7-methylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0321] Melting point: 147.5-148.5° C.

[0322] (Example 119)2-(4-chlorophenyl)-5-n-butyl-8-methylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0323] Melting point: 203.5-205° C.

[0324] (Example 120)5-n-butyl-7-methyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0325] Melting point: 156-157° C.

[0326] (Example 121)5-n-butyl-8-methyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0327] Melting point: 180-181° C.

[0328] (Example 122)5-n-butyl-2-(4-methylphenyl)-7-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0329] Melting point: 113-113.5° C.

[0330] (Example 123)5-n-butyl-2-(4-methylphenyl)-8-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0331] Melting point: 101.5-103.5° C.

[0332] (Example 124)5-n-butyl-2-(4-fluorophenyl)-7-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0333] Melting point: 105.5-106° C.

[0334] (Example 125)5-n-butyl-2-(4-fluorophenyl)-8-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0335] Melting point: 106.5-107.5° C.

[0336] (Example 126)5-n-butyl-2-(4-chlorophenyl)-7-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0337] Melting point: 131.5-132° C.

[0338] (Example 127)5-n-butyl-2-(4-chlorophenyl)-8-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0339] Melting point: 137-138° C.

[0340] (Example 128) ethyl2-(5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-7-yl)acetate

[0341] Melting point: 131.5-132.5° C.

[0342] (Example 129) ethyl2-(5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-8-yl)acetate

[0343] Melting point: 136-137° C.

[0344] (Example 130) ethyl2-[5-n-butyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-7-yl]acetate

[0345] Melting point: 139.5-140.5° C.

[0346] (Example 131) ethyl2-[5-n-butyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-8-yl]acetate

[0347] Melting point: 164-165° C.

[0348] (Example 132)5-n-butyl-7-(2-hydroxyethyl)-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0349] Melting point: 132-133° C.

[0350] (Example 133)5-n-butyl-8-(2-hydroxyethyl)-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0351] Melting point: 160.5-162° C.

[0352] (Example 134)5-n-butyl-2-(4-fluorophenyl)-7-(2-hydroxyethyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0353] Melting point: 150.5-151.5° C.

[0354] (Example 135)5-n-butyl-2-(4-fluorophenyl)-8-(2-hydroxyethyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0355] Melting point: 202-203° C.

[0356] (Example 136)5-n-butyl-7-(2-hydroxyethyl)-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0357] Melting point: 134-136° C.

[0358] (Example 137)5-n-butyl-8-(2-hydroxyethyl)-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0359] Melting point: 171-173° C.

[0360] (Example 138)5-n-butyl-2-(4-chlorophenyl)-7-(2-hydroxyethyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0361] Melting point: 164-164.5° C.

[0362] (Example 139)5-n-butyl-2-(4-chlorophenyl)-8-(2-hydroxyethyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0363] Melting point: 189-190.5° C.

[0364] (Example 140)5-n-butyl-7-(2-hydroxyethyl)-2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0365] Melting point: 147.5-148.5° C.

[0366] (Example 141)5-n-butyl-8-(2-hydroxyethyl)-2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0367] Melting point: 178-179° C.

[0368] (Example 142)5-n-butyl-8-ethyl-2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0369] Melting point: 127-128° C.

[0370] (Example 143)5-n-butyl-8-ethyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0371] Melting point: 128-129° C.

[0372] (Example 144)5-n-butyl-8-ethyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0373] Melting point: 146-147° C.

[0374] (Example 145)5-n-butyl-2-(4-chlorophenyl)-8-ethylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0375] Melting point: 141-142° C.

[0376] (Example 146)5-n-butyl-2-(4-methoxyphenyl)-8-n-propylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine

[0377] Melting point: 112-112.5° C.

Example 147

[0378] Preparation of4-(2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl)butyricAcid

[0379] 0.15 g of the compound (methyl4-[2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyrate)obtained in Example 89 was suspended in 3 ml of ethanol and 0.89 ml of a5% aqueous sodium hydroxide solution was added, followed by stirring atroom temperature for 4 hours. The reaction solution was diluted with 10ml of water and then acidified by adding hydrochloric acid. Thedeposited crystal was collected by filtration and then recrystallizedfrom hydrous ethanol to obtain 0.13 g of a desired compound as a crystal(melting point: 261.5-262.5° C.).

Examples 148 to 157

[0380] In the same manner as in Example 147, the following compoundswere prepared.

[0381] (Example 148)4-[2-(4-methoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyricacid

[0382] Melting point: 247.5-249° C.

[0383] (Example 149)4-[2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyricacid

[0384] Melting point: 253.5-255.5° C.

[0385] (Example 150)4-[2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]butyricacid

[0386] Melting point: 249-251° C.

[0387] (Example 151)2-(5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-7-yl)aceticacid

[0388] Melting point: 271-272.5° C.

[0389] (Example 152)2-(5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-8-yl)aceticacid

[0390] Melting point: >281° C. (with decomposition)

[0391] (Example 153)4-(2-phenyl-1,2,4-triazolo[1,5-c]quinazolin-5-yl)butyric acid

[0392] Melting point: 211-211.5° C.

[0393] (Example 154)4-[2-(4-bromophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyric acid

[0394] Melting point: 219-220° C.

[0395] (Example 155)4-[2-(4-fluorophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyric acid

[0396] Melting point: 225-226° C.

[0397] (Example 156)4-[2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]butyric acid

[0398] Melting point: 227-228° C.

[0399] (Example 157)2-(4-hydroxyphenyl)-5-n-pentyl-1,2,4-triazolo[1,5-c]quinazoline

[0400] Melting point: 214-215° C.

[0401] Data of ¹H-NMR spectrum (δ:ppm) of the compounds of the aboverespective Examples are shown below. Dimethyl sulfoxide-d6 (DMSO-d₆) orchloroform-d (CDCl₃) was used as a solvent in the measurement andtetramethylsilane was used as an internal reference.

Example 1 DMSO-d₆

[0402] 2.97 (3H, s), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.57 (1H, bs).

Example 2 DMSO-d₆

[0403] 1.45 (3H, t, J=7.4), 3.37 (2H, q, J=7.4), 7.5-7.6 (3H, m),8.2-8.3 (2H, m), 8.56 (1H, bs).

Example 3 DMSO-d₆

[0404] 1.07 (3H, t, J=7.4), 1.9-2.1 (2H, m), 3.3-3.4 (2H, m), 7.5-7.7(3H, m), 8.2-8.4 (2H, m), 8.56 (1H, bs).

Example 4 DMSO-d₆

[0405] 0.99 (3H, t, J=7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.56 (1H, bs).

Example 5 DMSO-d₆

[0406] 0.98 (3H, t, J=7.4), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.40 (2H, t, J=8.8), 8.29 (2H, dd, J=5.5, 8.8), 8.55 (1H, bs).

Example 6 DMSO-d₆

[0407] 0.98 (3H, t, J=7.4), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.3-3.4(2H, m), 7.75 (2H, d, J=8.5), 8.16 (2H, d, J=8.5), 8.54 (1H, bs).

Example 7 DMSO-d₆

[0408] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.63 (2H, d, J=8.6), 8.24 (2H, d, J=8.6), 8.55 (1H, bs).

Example 8 DMSO-d₆

[0409] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 2.40 (3H,s), 3.3-3.4 (2H, m), 7.37 (2H, d, J=8.1), 8.14 (2H, d, J=8.1), 8.54 (1H,bs).

Example 9 DMSO-d₆

[0410] 0.98 (3H, t, J=7.4), 1.34 (9H, s), 1.4-1.5 (2H, m), 1.9-2.0 (2H,m), 3.3-3.4 (2H, m), 7.58 (2H, d, J=8.5), 8.17 (2H, d, J=8.5), 8.55 (1H,bs).

Example 10 DMSO-d₆

[0411] 0.99 (3H, t, J=7.3), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.91 (2H, d, J=8.3), 8.42 (2H, d, J=8.3), 8.56 (1H, bs).

Example 11 DMSO-d₆

[0412] 0.99 (3H, t, J=7.3), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.4-7.6 (3H, m), 7.77 (2H, d, J=7.3), 7.87 (2H, d, J=8.4), 8.33(2H, d, J=8.4), 8.57 (1H, bs).

Example 12 DMSO-d₆

[0413] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 6.94 (2H, d, J=8.7), 8.09 (2H, d, J=8.7), 8.52 (1H, bs).

Example 13 DMSO-d₆

[0414] 0.98 (3H, t, J=7.4), 1.37 (3H, t, J=6.9), 1.4-1.5 (2H, m),1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.12 (2H, q, J=7.0), 7.08 (2H, d,J=8.9), 8.16 (2H, d, J=8.9), 8.53 (1H, bs).

Example 14 DMSO-d₆

[0415] 0.98 (3H, t, J=7.5), 1.01 (3H, t, J=7.5), 1.4-1.6 (2H, m),1.7-1.8 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.01 (2H, t, J=6.6),7.09 (2H, d, J=8.7), 8.16 (2H, d, J=8.7), 8.52 (1H, bs).

Example 15 DMSO-d₆

[0416] 0.99 (3H, t, J=7.4), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.76 (3H, s), 3.91 (6H, s), 7.52 (2H, s), 8.56 (1H, bs).

Example 16 DMSO-d₆

[0417] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.01 (6H,s), 3.3-3.4 (2H, m), 6.83 (2H, d, J=8.9), 8.06 (2H, d, J=8.9), 8.50 (1H,bs).

Example 17 DMSO-d₆

[0418] 0.99 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 8.39 (2H, d, J=9.0), 8.46 (2H, d, J=9.0), 8.58 (1H, bs).

Example 18 DMSO-d₆

[0419] 0.99 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.61 (1H, dd, J=5.0, 7.9), 8.5-8.6 (2H, m), 8.75 (1H, dd,J=1.7, 5.0), 9.40 (1H, d, J=2.1).

Example 19 DMSO-d₆

[0420] 0.98 (3H, t, J=7.4), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.47 (1H, dd, J=1.8, 3.4), 7.28 (1H, dd, J=0.6, 3.4), 7.96 (1H,dd, J=0.6, 1.8), 8.53 (1H, bs).

Example 20 DMSO-d₆

[0421] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.25 (1H, dd, J=3.3, 5.0), 7.79 (1H, dd, J=1.2, 5.0), 7.89 (1H,dd, J=1.2, 3.3), 8.55 (1H, bs).

Example 21 CDCl₃

[0422] 1.16 (3H, t, J=7.4), 2.0-2.1 (2H, m), 3.4-3.5 (2H, m), 7.5-7.6(3H, m), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01 (1H, bd, J=8.2), 8.3-8.4(2H, m), 8.58 (1H, dd, J=1.1, 8.0).

Example 22 DMSO-d₆

[0423] 0.99 (3H, t, J=7.3), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.5-7.6 (3H, m), 7.7-7.8 (1H, m), 7.9-8.0 (1H, m), 8.02 (1H,bd, J=8.0), 8.2-8.3 (2H, m), 8.47 (1H, dd, J=0.9, 7.9).

Example 23 CDCl₃

[0424] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.21 (2H, t, J=8.7), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01(1H, bd, J=8.2), 8.38 (2H, dd, J=5.4, 8.7), 8.55 (1H, dd, J=1.1, 8.0).

Example 24 CDCl₃

[0425] 1.03 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.4-7.5 (2H, m), 7.5-7.6 (1H, m), 7.6-7.7 (1H, m), 7.8-7.9 (1H,m), 8.03 (1H, bd, J=8.2), 8.0-8.1 (1H, m), 8.57 (1H, dd, J=1.5, 7.9).

Example 25 CDCl₃

[0426] 1.05 (3H, t, J=7.6), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.4-7.5 (2H, m), 7.7-7.8 (1H, m), 7.8-7.9 (1H, m), 8.01 (1H,bd, J=8.5), 8.2-8.3 (1H, m), 8.39 (1H, brs), 8.55 (1H, dd, J=5, 7.9).

Example 26 CDCl₃

[0427] 1.04 (3H, t, J=7.4), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.50 (2H, d, J=8.5), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.01(1H, bd, J=8.2), 8.33 (2H, d, J=8.5), 8.55 (1H, dd, J=0.9, 7.8).

Example 27 CDCl₃

[0428] 1.04 (3H, t, J=7.4), 1.5-1.6 (2H, m), 1.9-2.0 (2H, m), 3.4-3.5(2H, m), 7.66 (2H, d, J=8.6), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.01(1H, bd, J=8.1), 8.26 (2H, d, J=8.6), 8.55 (1H, dd, J=1.1, 8.1).

Example 28 CDCl₃

[0429] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.33 (2H, d, J=8.0), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.00(1H, bd, J=8.2), 8.27 (2H, d, J=8.0), 8.56 (1H, dd, J=1.0, 7.9).

Example 29 CDCl₃

[0430] 1.04 (3H, t, J=7.3), 1.39 (9H, s), 1.5-1.6 (2H, m), 2.0-2.1 (2H,m), 3.4-3.5 (2H, m), 7.55 (2H, d, J=8.5), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 8.00 (1H, bd, J=8.2), 8.30 (2H, d, J=8.5), 857 (1H, dd, J=1.3, 7.9).

Example 30 CDCl₃

[0431] 1.05 (3H, t, J=7.5), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.6-7.7 (1H, m), 7.77 (2H, d, J=7.9), 7.8-7.9 (1H, m), 8.01(1H, bd, J=8.3), 8.49 (2H, d, J=7.9), 8.55 (1H, dd, J=1.2, 7.9).

Example 31 CDCl₃

[0432] 1.05 (3H, t, J=7.5), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.3-7.4 (1H, m), 7.4-75 (2H, m), 7.6-7.7 (3H, m), 7.76 (2H, d,J=7.9), 7.7-7.8 (1H, m), 8.01 (1H, bd, J=8.3), 8.45 (2H, d, J=7.9), 8.58(1H, dd, J=1.2, 7.9).

Example 32 DMSO-d₆

[0433] 0.99 (3H, t, J=7.4), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 6.96 (2H, d, J=8.6), 7.7-7.8 (1H, m), 7.8-7.9 (1H, m), 7.99(1H, bd, J=8.2), 8.12 (2H, d, J=8.6), 8.43 (1H, bd, J=7.9).

Example 33 CDCl₃

[0434] 1.03 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 3.98 (3H, s), 7.1-7.2 (2H, m), 7.4-7.5 (1H, m), 7.67 (1H, bt,J=7.9), 7.7-7.8 (1H, m), 8.01 (1H, bd, J=8.2), 8.06 (1H, dd, J=1.8,7.6), 8.59 (1H, bd, J=7.9).

Example 34 CDCl₃

[0435] 1.04 (3H, t, J=7.4), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 3.90 (3H, s), 7.04 (2H, d, J=8.9), 7.6-7.7 (1H, m), 7.7-7.8(1H, m), 7.99 (1H, d, J=8.1), 8.32 (2H, bd, J=8.9), 856 (1H, dd, J=1.1,7.9).

Example 35 CDCl₃

[0436] 1.04 (3H, t, J=7.3), 1.47 (3H, t, J=7.0), 1.5-1.6 (2H, m),2.0-2.1 (2H, m), 3.4-3.5 (2H, m), 4.13 (2H, q, J=7.0), 7.03 (2H, d,J=8.9), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 7.99 (1H, bd, J=8.2), 8.31(2H, d, J=8.9), 8.55 (1H, dd, J=1.0, 8.0).

Example 36 CDCl₃

[0437] 1.04 (3H, t, J=7.3), 1.08 (3H, t, J=7.6), 1.5-1.6 (2H, m),1.8-1.9 (2H, m), 2.0-2.1 (2H, m); 3.4-3.5 (2H, m), 4.01 (2H, t, J=6.4),7.03 (2H, d, J=8.8), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 7.99 (1H, bd,J=8.2), 8.30 (2H, d, J=8.8), 8.55 (1H, dd, J=1.5, 7.9).

Example 37 CDCl₃

[0438] 1.05 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 3.94 (3H, s), 4.04 (6H, s), 7.64 (2H, s), 7.6-7.7 (1H, m),7.8-7.9 (1H, m), 8.01 (1H, bd, J=8.2), 8.57 (1H, dd, J=1.5, 7.9).

Example 38 CDCl₃

[0439] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.06 (6H,s), 3.4-3.5 (2H, m), 6.81 (2H, d, J=9.1), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 7.97 (1H, bd, J=8.2), 8.24 (2H, d, J=9.1), 855 (1H, dd, J=1.5, 7.9).

Example 39 CDCl₃

[0440] 1.05 (3H, t, J=7.4), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.7-7.8 (1H, m), 7.8-7.9 (1H, m), 8.04 (1H, bd, J=8.1), 8.38(2H, d, J=9.0), 8.5-8.6 (1H, m), 8.58 (2H, d, J=9.0).

Example 40 CDCl₃

[0441] 1.05 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.46 (1H, dd, J=5.0, 7.9), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m),8.02 (1H, bd, J=8.2), 8.56 (1H, dd, J=1.5, 7.9), 8.64 (1H, dt, J=7.9,2.1), 8.74 (1H, dd, J=2.1, 5.0), 9.59 (1H, bd, J=2.1).

Example 41 CDCl₃

[0442] 1.03 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 6.61 (1H, dd, J=1.8, 3.2), 7.30 (1H, dd, J=0.6, 3.2), 7.66 (1H,dd, J=0.6, 1.8), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01 (1H, bd, J=8.5),8.56 (1H, dd, J=1.5, 7.9).

Example 42 CDCl₃

[0443] 1.04 (3H, t, J=7.6), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.19 (1H, dd, J=3.8, 53), 7.49 (1H, dd, J=1.2, 5.3), 7.6-7.7(1H, m), 7.7-7.8 (1H, m), 7.9-8.0 (2H, m), 8.55 (1H, dd, J=1.5, 7.9).

Example 43 CDCl₃

[0444] 1.05 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.40 (1H, bt, J=8.2), 75-7.6 (3H, m), 7.75 (1H, dt, J=5.6,8.2), 7.82 (1H, bd, J=8.2), 8.4-8.5 (2H, m).

Example 44 CDCl₃

[0445] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.5-7.6 (3H, m), 7.68 (1H, bt, J=7.9), 7.72 (1H, dd, J=1.8,7.9), 7.93 (1H, dd, J=1.8, 7.9), 8.4-8.5 (2H, m).

Example 45 CDCl₃

[0446] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.5-7.6 (3H, m), 7.73 (1H, dd, J=2.6, 8.8), 7.93 (1H, d,J=8.8), 8.3-8.4 (2H, m), 8.55 (1H, d, J=2.6).

Example 46 CDCl₃

[0447] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.5-7.6 (3H, m), 7.64 (1H, dd, J=2.0, 8.8), 8.01 (1H, d,J=2.0), 8.3-8.4 (2H, m), 8.49 (1H, d, J=8.8).

Example 47 CDCl₃

[0448] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.5-7.6 (3H, m), 7.8-7.9 (2H, m), 8.3-8.4 (2H, m), 8.7-8.8 (1H,m).

Example 48 CDCl₃

[0449] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 4.06 (3H, s), 4.12 (3H, s), 7.41 (1H, s), 7.5-7.6 (3H, m), 7.86(1H, s), 8.3-8.4 (2H, m).

Example 49 CDCl₃

[0450] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.18 (3H,s), 3.4-3.5 (2H, m), 7.4-7.6 (4H, m), 7.66 (1H, bt, J=7.9), 7.84 (1H,bd, J=7.9), 8.4-8.5 (2H, m).

Example 50 CDCl₃

[0451] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 2.58 (3H,s), 3.4-3.5 (2H, m), 7.5-7.6 (4H, m), 7.81 (1H, bs), 8.3-8.4 (2H, m),8.44 (1H, d, J=8.2).

Example 51 DMSO-d₆

[0452] 0.97 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.5-7.6 (2H, m), 7.6-7.7 (1H, m), 8.08 (1H, dd, J=2.5, 7.1),8.57 (1H, bs).

Example 52 DMSO-d₆

[0453] 0.99 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.5-7.6 (2H, m), 8.1-8.2 (2H, m), 8.52 (1H, bs).

Example 53 DMSO-d₆

[0454] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.88 (3H, s), 7.11 (1H, bt, J=7.5), 7.22 (1H, bd, J=8.7), 7.52(1H, m), 7.93 (1H, dd, J=1.7, 75), 8.53 (1H, bs).

Example 54 DMSO-d₆

[0455] 0.99 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.87 (3H, s), 7.11 (1H, dd, J=2.5, 7.9), 7.48 (1H, bt, J=7.9),7.7-7.8 (1H, m), 7.84 (1H, bd, J=7.9), 8.56 (1H, bs).

Example 55 DMSO-d₆

[0456] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.85 (3H, s), 7.10 (2H, d, J=9.1), 8.17 (2H, d, J=9.1), 8.52(1H, bs).

Example 56 DMSO-d₆

[0457] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 2.55 (3H,s), 3.3-3.4 (2H, m), 7.41 (2H, d, J=8.7), 8.15 (2H, d, J=8.7), 8.53 (1H,bs).

Example 57 CDCl₃

[0458] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 3.95 (3H, s), 7.05 (1H, dd, J=2.6, 7.9), 7.44 (1H, t, J=7.9),7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 7.9-8.0 (1H, m), 8.0-8.1 (2H, m), 8.57(1H, dd, J=1.5, 8.2).

Example 58 CDCl₃

[0459] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 2.56 (3H,s), 3.4-3.5 (2H, m), 7.37 (2H, d, J=8.5), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 8.00 (1H, bd, J=8.2), 8.29 (2H, d, J=8.5), 856 (1H, dd, J=1.5, 7.9).

Example 59 DMSO-d₆

[0460] 7.5-7.6 (3H, m), 7.6-7.7 (3H, m), 8.2-8.3 (2H, m), 8.4-8.5 (2H,m), 8.65 (1H, bs).

Example 60 DMSO-d₆

[0461] 1.07 (3H, t, J=7.5), 1.9-2.0 (2H, m), 2.40 (3H, s), 3.3-3.4 (2H,m), 7.37 (2H, d, J=8.3), 8.14 (2H, d, J=8.3), 8.54 (1H, bs).

Example 61 CDCl₃

[0462] 1.05 (3H, t, J=7.5), 1.30 (3H, t, J=7.5), 1.5-1.6 (2H, m),2.0-2.1 (2H, m), 2.74 (2H, q, J=7.5), 3.3-3.4 (2H, m), 7.35 (2H, d,J=8.3), 8.26 (2H, d, J=8.3), 8.47 (1H, s).

Example 62 CDCl₃

[0463] 0.98 (3H, t, J=7.5), 1.05 (3H, t, J=7.5), 1.5-1.6 (2H, m),1.6-1.7 (2H, m), 2.0-2.1 (2H, m), 2.6-2.7 (2H, m), 3.4-3.5 (2H, m), 7.33(2H, d, J=8.3), 8.25 (2H, d, J=8.3), 8.47 (1H, s).

Example 63 DMSO-d₆

[0464] 1.45 (3H, t, J=7.5), 3.36 (2H, q, J=7.5), 3.85 (3H, s), 7.10 (2H,d, J=8.7), 8.18 (2H, d, J=8.7), 8.53 (1H, bs).

Example 64 DMSO-d₆

[0465] 1.44 (3H, t, J=7.5), 3.35 (2H, q, J=7.5), 7.61 (2H, d, J=8.3),8.22 (2H, d, J=8.3), 8.54 (1H, bs).

Example 65 DMSO-d₆

[0466] 1.44 (3H, t, J=7.5), 2.39 (3H, s), 3.36 (2H, q, J=7.5), 7.35 (2H,d, J=8.3), 8.12 (2H, d, J=8.3), 8.53 (1H, bs).

Example 66 CDCl₃

[0467] 1.58 (3H, t, J=7.6), 3.45 (2H, q, J=7.6), 7.65 (2H, d, J=8.5),7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.02 (1H, bd, J=8.2), 8.25 (2H, d,J=8.5), 8.5-8.6 (1H, m).

Example 67 CDCl₃

[0468] 1.59 (3H, t, J=7.3), 3.45 (2H, q, J=7.3), 7.21 (2H, t, J=8.8),7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.02 (1H, bd, J=8.2), 8.38 (2H, dd,J=5.6, 8.8), 8.56 (1H, dd, J=1.5, 7.9).

Example 68 CDCl₃

[0469] 1.58 (3H, t, J=7.3), 3.44 (2H, q, J=7.3), 7.49 (2H, d, J=8.5),7.68 (1H, bt, J=7.3), 7.8-7.9 (1H, m), 8.02 (1H, bd, J=8.2), 8.32 (2H,d, J=8.5), 8.5-8.6 (1H, m).

Example 69 CDCl₃

[0470] 1.59 (3H, t, J=7.6), 2.44 (3H, s), 3.46 (2H, q, J=7.6), 7.33 (2H,d, J=8.5), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01 (1H, bd, J=8.2), 8.27(2H, d, J=8.5), 8.57 (1H, dd, J=1.5, 7.9).

Example 70 DMSO-d₆

[0471] 1.48 (3H, t, J=7.5), 3.36 (2H, q, J=7.5), 6.95 (2H, d, J=8.7),7.7-7.8 (1H, m), 7.8-7.9 (1H, m), 8.00 (1H, bd, J=8.3), 8.12 (2H, d,J=8.7), 8.44 (1H, dd, J=1.2, 7.9).

Example 71 CDCl₃

[0472] 1.58 (3H, t, J=7.5), 3.44 (2H, q, J=7.5), 3.89 (3H, s), 7.03 (2H,d, J=8.7), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.00 (1H, bd, J=8.3), 8.31(2H, d, J=8.7), 8.55 (1H, dd, J=1.3, 75).

Example 72 CDCl₃

[0473] 1.47 (3H, t, J=7.0), 1.58 (3H, t, J=7.6), 3.45 (2H, q, J=7.6),4.13 (2H, q, J=7.0), 7.03 (2H, d, J=8.8), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 8.01 (1H, bd, J=7.9), 8.30 (2H, d, J=8.8), 8.56 (1H, dd, J=1.2,8.2).

Example 73 CDCl₃

[0474] 1.15 (3H, t, J=7.3), 2.0-2.1 (2H, m), 3.3-3.4 (2H, m), 7.5-7.6(3H, m), 7.74 (1H, dd, J=2.3, 8.8), 7.94 (1H, d, J=8.8), 8.3-8.4 (2H,m), 8.55 (1H, d, J=2.3).

Example 74 CDCl₃

[0475] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.21 (2H, t, J=8.8), 7.73 (1H, dd, J=2.3, 8.8), 7.93 (1H, d,J=8.8), 8.36 (2H, dd, J=5.6, 8.8), 8.52 (1H, d, J=2.3).

Example 75 CDCl₃

[0476] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.49 (2H, d, J=8.8), 7.73 (1H, dd, J=2.3, 8.8), 7.93 (1H, d,J=8.8), 8.29 (2H, d, J=8.8), 8.51 (1H, d, J=2.3).

Example 76 CDCl₃

[0477] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.65 (2H, d, J=8.5), 7.73 (1H, dd, J=2.3, 8.8), 7.93 (1H, d,J=8.8), 8.23 (2H, d, J=8.5), 8.51 (1H, d, J=2.3).

Example 77 CDCl₃

[0478] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 2.45 (3H,s), 3.4-3.5 (2H, m), 7.33 (2H, d, J=8.2), 7.72 (1H, dd, J=2.3, 8.8),7.92 (1H, d, J=8.8), 8.25 (2H, d, J=8.2), 8.54 (1H, d, J=2.3).

Example 78 CDCl₃

[0479] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 3.90 (3H, s), 7.04 (2H, d, J=8.8), 7.72 (1H, dd, J=2.3, 8.8),7.92 (1H, d, J=8.8), 8.30 (2H, d, J=8.8), 8.53 (1H, d, J=2.3).

Example 79 CDCl₃

[0480] 1.15 (3H, t, J=7.3), 2.0-2.1 (2H, m), 3.3-3.4 (2H, m), 7.5-7.6(3H, m), 7.64 (1H, dd, J=2.0, 85), 8.02 (1H, d, J=2.0), 8.3-8.4 (2H, m),8.50 (1H, d, J=8.85).

Example 80 CDCl₃

[0481] 1.04 (3H, t, J=7.6), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.21 (2H, t, J=8.8), 7.64 (1H, dd, J=2.1, 85), 8.02 (1H, d,J=2.1), 8.36 (2H, dd, J=5.3, 8.8), 8.48 (1H, d, J=8.5).

Example 81 CDCl₃

[0482] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.49 (2H, d, J=8.5), 7.63 (1H, dd, J=2.0, 85), 8.00 (1H, d,J=2.0), 8.29 (2H, d, J=8.5), 8.45 (1H, d, J=8.5).

Example 82 CDCl₃

[0483] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.6-7.7 (1H, m), 7.65 (2H, d, J=8.2), 8.02 (1H, d, J=1.8), 8.24(2H, d, J=8.2), 8.47 (1H, d, J=8.8).

Example 83 CDCl₃

[0484] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 2.45 (3H,s), 3.4-3.5 (2H, m), 7.33 (2H, d, J=8.2), 7.63 (1H, dd, J=1.8, 85), 8.00(1H, d, J=1.8), 8.25 (2H, d, J=8.2), 8.49 (1H, d, J=8.5).

Example 84 CDCl₃

[0485] 1.04 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 3.90 (3H, s), 7.04 (2H, d, J=8.8), 7.62 (1H, dd, J=2.0, 85),8.00 (1H, d, J=2.0), 8.29 (2H, d, J=8.8), 8.47 (1H, d, J=8.5).

Example 85 CDCl₃

[0486] 1.06 (3H, t, J=7.3), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.5-7.6 (3H, m), 8.14 (1H, d, J=9.1), 8.3-8.4 (214, m), 8.59(1H, dd, J=2.6, 9.1), 9.47 (1H, d, J=2.6).

Example 86 CDCl₃

[0487] 1.57 (3H, t, J=7.6), 3.43 (2H, q, J=7.6), 7.49 (2H, d, J=8.2),7.74 (1H, dd, J=2.3, 8.8), 7.95 (1H, d, J=8.8), 8.30 (2H, d, J=8.2),8.52 (1H, d, J=2.3).

Example 87 DMSO-d₆

[0488] 0.92 (3H, t, J=7.1), 1.4-1.5 (4H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.56 (1H, bs).

Example 88 CDCl₃

[0489] 0.92 (3H, t, J=7.1), 1.3-1.5 (4H, m), 1.5-1.6 (2H, m), 2.0-2.1(2H, m), 3.4-3.5 (2H, m), 7.5-7.6 (3H, m), 8.3-8.4 (2H, m), 8.46 (1H,s).

Example 89 DMSO-d₆

[0490] 2.2-2.3 (2H, m), 2.58 (2H, t, J=7.5), 3.41 (2H, t, J=7.5), 3.58(3H, s), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.57 (1H, bs).

Example 90 DMSO-d₆

[0491] 2.2-2.3 (2H, m), 2.57 (2H, t, J=7.5), 3.38 (2H, t, J=7.5), 3.57(3H, s), 3.85 (3H, s), 7.11 (2H, d, J=9.1), 8.18 (2H, d, J=9.1), 8.53(1H, bs).

Example 91 DMSO-d₆

[0492] 2.2-2.3 (2H, m), 2.57 (2H, t, J=7.5), 3.39 (2H, t, J=7.5), 3.57(3H, s), 7.63 (2H, d, J=8.3), 8.25 (2H, d, J=8.3), 8.55 (1H, bs).

Example 92 DMSO-d₆

[0493] 2.2-2.3 (2H, m), 2.40 (3H, s), 2.57 (2H, t, J=7.5), 3.39 (2H, t,J=7.5), 3.57 (3H, s), 7.37 (2H, d, J=7.9), 8.14 (2H, d, J=7.9), 8.54(1H, bs).

Example 93 CDCl₃

[0494] 0.96 (3H, t, J=7.1), 1.4-1.6 (4H, m), 2.0-2.1 (2H, m), 3.4-3.5(2H, m), 7.5-7.6 (3H, m), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.00 (1H,bd, J=8.3), 8.3-8.4 (2H, m), 8.57 (1H, dd, J=0.8, 7.9).

Example 94 CDCl₃

[0495] 0.92 (3H, t, J=7.0), 1.3-1.5 (4H, m), 1.5-1.6 (2H, m), 2.0-2.1(2H, m), 3.4-3.5 (2H, m), 7.5-7.6 (3H, m), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 8.00 (1H, bd, J=8.2), 8.3-8.4 (2H, m), 8.57 (1H, dd, J=1.5, 8.2).

Example 95 CDCl₃

[0496] 0.96 (3H, t, J=7.3), 1.4-1.6 (4H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.21 (2H, t, J=8.8), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.00(1H, bd, J=8.2), 8.37 (2H, dd, J=5.6, 8.8), 8.54 (1H, dd, J=1.5, 8.2).

Example 96 CDCl₃

[0497] 2.4-2.5 (2H, m), 2.60 (2H, t, J=7.3), 3.50 (2H, t, J=7.3), 3.67(3H, s), 7.5-7.6 (3H, m), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.02 (1H,bd, J=8.2), 8.3-8.4 (2H, m), 8.58 (1H, dd, J=1.5, 7.9).

Example 97 CDCl₃

[0498] 2.4-2.5 (2H, m), 2.60 (2H, t, J=7.6), 3.48 (2H, t, J=7.6), 3.67(3H, s), 7.65 (2H, d, J=8.2), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.00(1H, bd, J=8.2), 8.24 (2H, d, J=8.2), 8.54 (1H, dd, J=1.5, 8.2).

Example 98 CDCl₃

[0499] 2.4-2.5 (2H, m), 2.60 (2H, t, J=7.3), 3.48 (2H, t, J=7.3), 3.67(3H, s), 7.21 (2H, t, J=9.1), 7.7-7.8 (1H, m), 7.8-7.9 (1H, m), 8.00(1H, bd, J=8.5), 8.37 (2H, dd, J=5.6, 9.1), 8.5-8.6 (1H, m).

Example 99 CDCl₃

[0500] 2.4-2.5 (2H, m), 2.61 (2H, t, J=7.3), 3.48 (2H, t, J=7.6), 3.67(3H, s), 7.49 (2H, d, J=8.2), 7.69 (1H, bt, J=7.3), 7.8-7.9 (1H, m),8.01 (1H, bd, J=8.2), 8.31 (2H, d, J=8.2), 8.5-8.6 (1H, m).

Example 100 CDCl₃

[0501] 2.4-2.5 (2H, m), 2.44 (3H, s), 2.60 (2H, t, J=7.6), 3.49 (2H, t,J=7.3), 3.67 (3H, s), 7.32 (2H, d, J=8.2), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 8.00 (1H, bd, J=8.2), 8.26 (2H, d, J=8.2), 8.56 (1H, dd, J=0.9,7.9).

Example 101 CDCl₃

[0502] 0.96 (3H, t, J=7.3), 1.4-1.6 (4H, m), 2.0-2.1 (2H, m), 2.45 (3H,s), 3.4-3.5 (2H, m), 7.33 (2H, d, J=8.2), 7.6-7.7 (1H, m), 7.7-7.8 (1H,m), 8.00 (1H, bd, J=8.2), 8.27 (2H, d, J=8.2), 856 (1H, dd, J=1.5, 7.9).

Example 102 CDCl₃

[0503] 0.96 (3H, t, J=7.3), 1.4-1.6 (4H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.65 (2H, d, J=8.5), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01(1H, bd, J=8.5), 8.26 (2H, d, J=8.5), 8.54 (1H, dd, J=1.5, 8.2).

Example 103 CDCl₃

[0504] 0.96 (3H, t, J=7.3), 1.4-1.6 (4H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 7.49 (2H, d, J=8.2), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01(1H, bd, J=8.5), 8.32 (2H, d, J=8.2), 8.54 (1H, dd, J=1.5, 7.9).

Example 104 CDCl₃

[0505] 2.3-2.5 (2H, m), 2.60 (2H, t, J=7.3), 3.46 (2H, t, J=7.3), 3.67(3H, s), 7.49 (2H, d, J=8.5), 7.74 (1H, dd, J=2.3, 8.8), 7.93 (1H, d,J=8.8), 8.29 (2H, d, J=8.5), 8.52 (1H, d, J=2.3).

Example 105 CDCl₃

[0506] 0.96 (3H, t, J=7.0), 1.4-1.6 (4H, m), 2.0-2.1 (2H, m), 3.3-3.4(2H, m), 3.90 (3H, s), 7.04 (2H, d, J=9.1), 7.6-7.7 (1H, m), 7.7-7.8(1H, m), 7.99 (1H, bd, J=8.5), 8.32 (2H, d, J=9.1), 8.55 (1H, dd, J=0.9,7.9).

Example 106 CDCl₃

[0507] 0.96 (3H, t, J=7.3), 1.47 (3H, t, J=7.0), 1.4-1.6 (4H, m),2.0-2.1 (2H, m), 3.3-3.4 (2H, m), 4.12 (2H, q, J=7.0), 7.02 (2H, d,J=8.5), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 7.99 (1H, bd, J=8.2), 8.30(2H, d, J=8.5), 8.54 (1H, bd, J=7.9).

Example 107 CDCl₃

[0508] 0.95 (3H, t, J=7.1), 0.96 (3H, t, J=7.1), 1.4-1.6 (8H, m),1.7-1.8 (2H, m), 2.0-2.1 (2H, m), 2.5-2.6 (2H, m), 3.4-3.5 (2H, m), 7.26(2H, d, J=8.7), 7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.01 (1H, bd, J=7.9),8.41 (2H, d, J=8.7), 8.56 (1H, dd, J=0.8, 7.9).

Example 108 DMSO-d₆

[0509] 0.99 (3H, t, J=7.3), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 4.10 (3H, s), 7.40 (2H, t, J=8.8), 8.29 (2H, dd, J=5.6, 8.8),8.45 (1H, s).

Example 109 DMSO-d₆

[0510] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.2-3.3(2H, m), 4.17 (3H, s), 7.39 (2H, t, J=8.8), 8.25 (2H, dd, J=5.6, 8.8),8.82 (1H, s).

Example 110 DMSO-d₆

[0511] 0.99 (3H, t, J=7.3), 1.5-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 4.11 (3H, s), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.47 (1H, s).

Example 111 DMSO-d₆

[0512] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 4.17 (3H, s), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.84 (1H, s).

Example 112 DMSO-d₆

[0513] 0.86 (3H, t, J=7.6), 0.99 (3H, t, J=7.3), 1.4-1.5 (2H, m),1.9-2.0 (4H, m), 3.3-3.4 (2H, m), 4.45 (2H, t, J=7.0), 7.5-7.6 (3H, m),8.2-8.3 (2H, m), 8.48 (1H, s).

Example 113 DMSO-d₆

[0514] 0.88 (3H, t, J=7.3), 0.99 (3H, t, J=7.3), 1.4-1.5 (2H, m),1.9-2.0 (4H, m), 3.3-3.4 (2H, m), 4.39 (2H, t, J=7.0), 7.5-7.6 (3H, m),8.2-8.3 (2H, m), 8.90 (1H, s).

Example 114 DMSO-d₆

[0515] 0.99 (3H, t, J=7.6), 1.49 (3H, t, J=7.3), 1.4-1.5 (2H, m),1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.52 (2H, q, J=7.3), 7.5-7.6 (3H, m),8.2-8.3 (2H, m), 8.48 (1H, s).

Example 115 DMSO-d₆

[0516] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.53 (3H, t, J=7.3),1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.46 (2H, q, J=7.3), 7.5-7.6 (3H, m),8.2-8.3 (2H, m), 8.91 (1H, s).

Example 116 DMSO-d₆

[0517] 0.99 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 5.71 (2H, s), 7.2-7.4 (5H, m), 7.5-7.6 (3H, m), 8.2-8.3 (2H,m), 8.51 (1H, s).

Example 117 DMSO-d₆

[0518] 0.97 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.8-1.9 (2H, m), 3.2-3.3(2H, m), 5.65 (2H, s), 7.3-7.4 (5H, m), 7.5-7.6 (3H, m), 8.2-8.3 (2H,m), 9.05 (1H, s).

Example 118 DMSO-d₆

[0519] 0.99 (3H, t, J=7.6), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 4.08 (3H, s), 7.60 (2H, d, J=8.5), 8.20 (2H, d, J=8.5), 8.42(1H, s).

Example 119 DMSO-d₆

[0520] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.2-3.3(2H, m), 4.17 (3H, s), 7.62 (2H, d, J=8.5), 8.21 (2H, d, J=8.5), 8.83(1H, s).

Example 120 DMSO-d₆

[0521] 0.99 (3H, t, J=7.3), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 2.40 (3H,s), 3.3-3.4 (2H, m), 4.10 (3H, s), 7.38 (2H, d, J=7.9), 8.15 (2H, d,J=7.9), 8.45 (1H, s).

Example 121 DMSO-d₆

[0522] 0.97 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 2.39 (3H,s), 3.2-3.3 (2H, m), 4.16 (3H, s), 7.36 (2H, d, J=7.9), 8.11 (2H, d,J=7.9), 8.81 (1H, s).

Example 122 DMSO-d₆

[0523] 0.86 (3H, t, J=7.5), 0.99 (3H, t, J=7.5), 1.4-1.6 (2H, m),1.9-2.0 (4H, m), 2.40 (3H, s), 3.3-3.4 (2H, m), 4.45 (2H, t, J=7.1),7.38 (2H, d, J=7.9), 8.15 (2H, d, J=7.9), 8.46 (1H, s).

Example 123 DMSO-d₆

[0524] 0.88 (3H, t, J=7.5), 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m),1.8-2.0 (4H, m), 2.39 (3H, s), 3.2-3.3 (2H, m), 4.38 (2H, t, J=7.1),7.36 (2H, d, J=7.9), 8.11 (2H, d, J=7.9), 8.87 (1H, s).

Example 124 DMSO-d₆

[0525] 0.86 (3H, t, J=7.5), 0.99 (3H, t, J=7.5), 1.4-1.6 (2H, m),1.9-2.0 (4H, m), 3.3-3.4 (2H, m), 4.45 (2H, t, J=7.1), 7.40 (2H, t,J=8.7), 8.30 (2H, dd, J=5.4, 8.7), 8.47 (1H, s).

Example 125 DMSO-d₆

[0526] 0.88 (3H, t, J=7.5), 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m),1.9-2.0 (4H, m), 3.2-3.3 (2H, m), 439 (2H, t, J=7.1), 7.39 (2H, t,J=8.7), 8.26 (2H, dd, J=5.4, 8.7), 8.89 (1H, s).

Example 126 DMSO-d₆

[0527] 0.86 (3H, t, J=7.5), 0.98 (3H, t, J=7.5), 1.4-1.6 (2H, m),1.9-2.0 (4H, m), 3.3-3.4 (2H, m), 4.45 (2H, t, J=7.1), 7.61 (2H, d,J=8.7), 8.25 (2H, d, J=8.7), 8.47 (1H, s).

Example 127 DMSO-d₆

[0528] 0.88 (3H, t, J=7.5), 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m),1.9-2.0 (4H, m), 3.2-3.3 (2H, m), 439 (2H, t, J=7.1), 7.63 (2H, d,J=8.7), 8.22 (2H, d, J=8.7), 8.90 (1H, s).

Example 128 DMSO-d₆

[0529] 0.97 (3H, t, J=7.3), 1.22 (3H, t, J=7.0), 1.4-1.5 (2H, m),1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.19 (2H, q, J=7.0), 5.41 (2H, s),7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.56 (1H, s).

Example 129 DMSO-d₆

[0530] 0.99 (3H, t, J=7.3), 1.25 (3H, t, J=7.0), 1.4-1.5 (2H, m),1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.21 (2H, q, J=7.0), 5.43 (2H, s),7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.89 (1H, s).

Example 130 DMSO-d₆

[0531] 0.97 (3H, t, J=7.3), 1.22 (3H, t, J=7.0), 1.4-1.5 (2H, m),1.9-2.0 (2H, m), 3.3-3.4 (2H, m), 4.19 (2H, q, J=7.0), 5.41 (2H, s),7.41 (2H, t, J=8.8), 8.30 (2H, dd, J=5.6, 8.8), 8.55 (1H, s).

Example 131 DMSO-d₆

[0532] 0.98 (3H, t, J=7.3), 1.24 (3H, t, J=7.0), 1.4-1.5 (2H, m),1.9-2.0 (2H, m), 3.2-3.3 (2H, m), 4.21 (2H, q, J=7.0), 5.43 (2H, s),7.40 (2H, t, J=8.8), 8.27 (2H, dd, J=5.6, 8.8), 8.88 (1H, s).

Example 132 DMSO-d₆

[0533] 0.99 (3H, t, J=7.6), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.91 (2H, bq, J=5.6), 4.52 (2H, bt, J=5.6), 4.93 (1H, bt,J=5.6), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.46 (1H, s).

Example 133 DMSO-d₆

[0534] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.90 (2H, bq, J=5.3), 4.47 (2H, bt, J=5.3), 5.03 (1H, bt,J=5.3), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.83 (1H, s).

Example 134 DMSO-d₆

[0535] 0.99 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.91 (2H, bq, J=5.6), 4.51 (2H, bt, J=5.6), 4.92 (1H, bt,J=5.6), 7.38 (2H, t, J=8.8), 8.26 (2H, dd, J=5.6, 8.8), 8.45 (1H, s).

Example 135 DMSO-d₆

[0536] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.2-3.3(2H, m), 3.90 (2H, bq, J=5.3), 4.46 (2H, bt, J=5.3), 5.03 (1H, bt,J=5.3), 7.39 (2H, t, J=8.8), 8.25 (2H, dd, J=5.6, 8.8), 8.82 (1H, s).

Example 136 DMSO-d₆

[0537] 0.99 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 2.40 (3H,s), 3.3-3.4 (2H, m), 3.91 (2H, bq, J=5.9), 4.52 (2H, bt, J=5.9), 4.90(1H, bt, J=5.9), 7.37 (2H, d, J=8.2), 8.14 (2H, d, J=8.2), 8.46 (1H, s).

Example 137 DMSO-d₆

[0538] 0.98 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 2.39 (3H,s), 3.2-3.3 (2H, m), 3.90 (2H, bt, J=5.6), 4.46 (2H, bt, J=5.6), 7.36(2H, d, J=8.2), 8.11 (2H, d, J=8.2), 8.81 (1H, s).

Example 138 DMSO-d₆

[0539] 0.99 (3H, t, J=7.5), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.91 (2H, bq, J=5.8), 4.53 (2H, bt, J=5.8), 4.90 (1H, bt,J=5.8), 7.63 (2H, d, J=8.3), 8.25 (2H, d, J=8.3), 8.47 (1H, s).

Example 139 DMSO-d₆

[0540] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.2-3.3(2H, m), 3.9-4.0 (2H, m), 4.46 (2H, bt, J=5.4), 5.0-5.1 (1H, m), 7.63(2H, d, J=8.7), 8.23 (2H, d, J=8.7), 8.83 (1H, s).

Example 40 DMSO-d₆

[0541] 0.99 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 3.85 (3H, s), 3.91 (2H, bq, J=5.8), 4.52 (2H, bt, J=5.8), 4.90(1H, bt, J=5.8), 7.11 (2H, d, J=8.7), 8.18 (2H, d, J=8.7), 8.45 (1H, s).

Example 141 DMSO-d₆

[0542] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.2-3.3(2H, m), 3.85 (3H, s), 3.8-3.9 (2H, m), 4.46 (2H, bt, J=5.4), 5.0-5.1(1H, m), 7.10 (2H, d, J=9.1), 8.15 (2H, d, J=9.1), 8.80 (1H, s).

Example 142 DMSO-d₆

[0543] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.53 (3H, t, J=7.5),1.9-2.0 (2H, m), 3.2-3.3 (2H, m), 3.85 (3H, s), 4.45 (2H, q, J=7.5),7.11 (2H, d, J=8.7), 8.16 (2H, d, J=8.7), 8.88 (1H, s).

Example 143 DMSO-d₆

[0544] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.53 (3H, t, J=7.5),1.9-2.0 (2H, m), 2.40 (3H, s), 3.2-3.3 (2H, m), 4.46 (2H, q, J=7.5),7.37 (2H, d, J=7.9), 8.12 (2H, d, J=7.9), 8.89 (1H, s).

Example 144 DMSO-d₆

[0545] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.53 (3H, t, J=7.5),1.9-2.0 (2H, m), 3.2-3.3 (2H, m), 4.46 (2H, q, J=7.5), 7.40 (2H, t,J=8.7), 8.26 (2H, dd, J=5.4, 8.7), 8.90 (1H, s).

Example 145 DMSO-d₆

[0546] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.53 (3H, t, J=7.5),1.9-2.0 (2H, m), 3.2-3.3 (2H, m), 4.46 (2H, q, J=7.5), 7.63 (2H, d,J=8.7), 8.23 (2H, d, J=8.7), 8.90 (1H, s).

Example 146 DMSO-d₆

[0547] 0.87 (3H, t, J=7.5), 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m),1.8-2.0 (4H, m), 3.2-3.3 (2H, m), 3.85 (3H, s), 4.38 (2H, t, J=7.0),7.11 (2H, d, J=8.7), 8.16 (2H, d, J=8.7), 8.88 (1H, s).

Example 147 DMSO-d₆

[0548] 2.1-2.3 (2H, m), 2.48 (2H, t, J=7.5), 3.40 (2H, t, J=7.5),7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.56 (1H, bs).

Example 148 DMSO-d₆

[0549] 2.1-2.2 (2H, m), 2.47 (2H, t, J=7.5), 3.38 (2H, t, J=7.5), 3.85(3H, s), 7.11 (2H, d, J=8.7), 8.19 (2H, d, J=8.7), 8.53 (1H, bs).

Example 149 DMSO-d₆

[0550] 2.1-2.2 (2H, m), 2.47 (2H, t, J=7.5), 3.39 (2H, t, J=7.5), 7.63(2H, d, J=8.3), 8.26 (2H, d, J=8.3), 8.56 (1H, bs).

Example 150 DMSO-d₆

[0551] 2.1-2.2 (2H, m), 2.40 (3H, s), 2.47 (2H, t, J=7.5), 3.39 (2H, t,J=7.5), 7.37 (2H, d, J=7.9), 8.15 (2H, d, J=7.9), 8.54 (1H, bs).

Example 151 DMSO-d₆

[0552] 0.98 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 5.29 (2H, s), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.52 (1H, s).

Example 152 DMSO-d₆

[0553] 0.97 (3H, t, J=7.5), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.2-3.3(2H, m), 5.29 (2H, s), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.84 (1H, s).

Example 153 DMSO-d₆

[0554] 2.2-2.3 (2H, m), 2.50 (2H, t, J=7.5), 3.40 (2H, t, J=7.5),7.5-7.6 (3H, m), 7.77 (1H, bt, J=7.9), 7.91 (1H, bt, J=7.9), 8.01 (1H,bd, J=7.9), 8.2-8.3 (2H, m), 8.46 (1H, bd, J=7.9).

Example 154 DMSO-d₆

[0555] 2.2-2.3 (2H, m), 2.49 (2H, t, J=7.5), 3.39 (2H, t, J=7.5),7.7-7.8 (1H, m), 7.77 (2H, d, J=8.3), 7.9-8.0 (1H, m), 8.01 (1H, bd,J=8.3), 8.20 (2H, d, J=8.3), 8.45 (1H, bd, J=7.9).

Example 155 DMSO-d₆

[0556] 2.2-2.3 (2H, m), 2.49 (2H, t, J=7.5), 3.39 (2H, t, J=7.5), 7.41(2H, t, J=8.7), 7.78 (1H, bt, J=7.5), 7.92 (1H, bt, J=7.5), 8.01 (1H,bd, J=7.5), 8.32 (2H, dd, J=5.8, 8.7), 8.46 (1H, bd, J=7.5).

Example 156 DMSO-d₆

[0557] 2.2-2.3 (2H, m), 2.49 (2H, t, J=7.5), 3.38 (2H, t, J=7.5), 7.63(2H, d, J=8.3), 7.77 (1H, bt, J=7.9), 7.91 (1H, bt, J=7.9), 8.00 (1H,bd, J=7.9), 8.26 (2H, d, J=8.3), 8.44 (1H, bd, J=7.9).

Example 157 DMSO-d₆

[0558] 0.91 (3H, t, J=7.1), 1.3-1.5 (4H, m), 1.9-2.0 (2H, m), 3.3-3.4(2H, m), 6.94 (2H, d, J=8.7), 7.75 (1H, bt, J=7.9), 7.8-7.9 (1H, m),7.99 (1H, bd, J=8.3), 8.11 (2H, d, J=8.7), 8.44 (1H, dd, J=0.8, 7.9).

EXPERIMENT EXAMPLE

[0559] Adenosine A3 Receptor Binding Capacity Test of TriazolopurineDerivative (1)

[0560] According to the method described in Molecular Pharmacology, 45,978 (1994), an adenosine A3 receptor binding capacity test wasperformed.

[0561] A cell membrane of human renal endothelial cells HEK-293transformed with plasmid coding an adenosine A3 receptor was isolated ina Tris-hydrochloric acid buffer (pH 7.7) in accordance with aconventional method, and then the cell membrane was treated withN⁶-(4-aminobenzyl)-9-[5-(methylcarbonyl)-β-D-ribofuranosyl]adenine(AB-MECA) labelled with ¹²⁵I to prepare a cell membrane bound with thecompound.

[0562] Then, this cell membrane and a test compound were incubated andthe amount of [¹²⁵] AB-MECA liberated was measured. The concentration ofthe test compound when 50% of [¹²⁵I] AB-MECA is liberated, IC₅₀, wasdetermined from the measured value of the test compound at eachconcentration.

[0563] The adenosine A2 receptor binding capacity of the test compoundwere measured according to the method described in Archives ofPharmacology, 336, 204 (1987) and The Journal of Pharmacology andExperimental Therapeutics, 251 (3), 888 (1989) and then evaluated asIC₅₀. The measurement results are shown in the following tables. TABLE 1Receptor Binding Capacity (IC₅₀) (nM) Example No. Adenosine A2 AdenosineA3 4 189 <10 5 >10000 <10 6 >10000 <10 7 >10000 19 8 >10000 <10 9 >10000154 10 >10000 132 13 2723 <10 22 >10000 255 23 >10000 28 26 >10000 2627 >10000 <10 28 >10000 34 31 >10000 144 32 5311 10 34 >10000 15535 >10000 35 37 1445 199 45 >10000 45 46 >10000 48 47 >10000 9350 >10000 109 54 2495 <10 55 2569 <10 61 >10000 12 62 >10000 4273 >10000 71 74 >10000 63 75 >10000 28 76 >10000 22 77 >10000 2378 >10000 33 83 >10000 30 84 >10000 34 87 2859 <10 93 >10000 37 113 452612 115 1563 <10 133 4160 24 152 >10000 32

Preparation Example 1

[0564] (Preparation of Tablets)

[0565] Two-thousands tablets, each of which contains 300 mg of thecompound(5-n-butyl-2-phenylpyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine)obtained in Example 4 as an active ingredient, were prepared accordingto the following formulation. Compound obtained in Example 4 600 gLactose (Japanese Pharmacopoeia)  67 g Cornstarch (JapanesePharmacopoeia)  33 g Calcium carboxymethylcellulose  25 g (JapanesePharmacopoeia) Methylcellulose (Japanese Pharmacopoeia)  12 g Magnesiumstearate (Japanese Pharmacopoeia)  3 g

[0566] According to the formulation described above, desired tabletswere obtained by sufficiently mixing the compound obtained in Example 4,lactose, cornstarch and calcium carboxymethylcellulose, granulating theresulting mixture using an aqueous methylcellulose, passing the granulesthrough a #24 mesh sieve, admixing the granules with magnesium stearateand compressing the admixture into tablets.

Preparation Example 2

[0567] (Preparation of capsules)

[0568] Two-thousands hard gelatin capsules, each of which contains 200mg of the compound(5-n-butyl-2-(3,4,5-trimethoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline)obtained in Example 37 as an active ingredient, were prepared accordingto the following formulation. Compound obtained in Example 37 400 gCrystalline cellulose (Japanese Pharmacopoeia)  60 g Cornstarch(Japanese Pharmacopoeia)  34 g Talc (Japanese Pharmacopoeia)  4 gMagnesium stearate (Japanese Pharmacopoeia)  2 g

[0569] According to the formulation described above, desired capsuleswere obtained by pulverizing the respective ingredients to form powders,mixing the powders to obtain an uniform mixture and filling a gelatincapsule for oral administration having a desired size with the mixture.

Preparation Example 3

[0570] (Preparation of Opthalmic Solutions)

[0571] Opthalmic solutions were prepared by dissolving 100 g of thecompound obtained in Example 152, 10 g of benzalkonium chloride, 560 gof sodium bihydrogenphosphate and 800 g of potassium bihydrogenphosphatein water for injection to make 100 l and filling a container with thesolution.

1. Triazoloquinazoline and pyrazolotriazolopyrimidine derivativesrepresented by the general formula (1):

wherein R¹ represents a lower alkyl group, a phenyl group, a loweralkoxycarbonyl lower alkyl group, or a carboxy lower alkyl group; R²represents a pyridyl group, a furyl group, a thienyl group, or a phenylgroup which optionally has 1 to 3 groups selected from lower alkylgroup, halogen atom, phenyl group, halogen-substituted lower alkylgroup, hydroxy group, lower alkoxy group, N,N-di lower alkylamino group,lower alkylthio group, lower alkanoyloxy group and nitro group as asubstituent; A represents a pyrazole ring which is optionallysubstituted with a group selected from lower alkyl group, phenyl loweralkyl group, lower alkoxycarbonyl lower alkyl group, carboxy lower alkylgroup and hydroxy lower alkyl group as a substituent, or a benzene ringwhich is optionally substituted with 1 to 2 groups selected from halogenatom, lower alkyl group, nitro group and lower alkoxy group as asubstituent; with the exception that A is a benzene ring, R² is apyridyl group or a phenyl group, and R¹ is a methyl group, an ethylgroup or a phenyl group.
 2. Triazoloquinazoline andpyrazolotriazolopyrimidine derivatives according to claim 1, wherein thepyrazolotriazolopyrimidine derivative is represented by the followinggeneral formula (1-1):

wherein R¹ and R² are as defined above.
 3. Triazoloquinazoline andpyrazolotriazolopyrimidine derivatives according to claim 1 or 2,wherein R² is a phenyl group which optionally have one group selectedfrom lower alkyl group, halogen atom, halogen-substituted lower alkylgroup and hydroxy group as a substituent, or phenyl group which has 1 to3 lower alkoxy groups.
 4. Triazoloquinazoline andpyrazolotriazolopyrimidine derivatives according to claim 3, wherein Ais a pyrazole ring, or a benzene ring which is optionally substitutedwith one halogen atom as a substituent.
 5. Triazoloquinazoline andpyrazolotriazolopyrimidine derivatives according to claim 4, wherein R¹is an n-butyl group and R² is a phenyl group which optionally has onegroup selected from lower alkoxy group, lower alkyl group, halogen atomand hydroxy group as a substituent.
 6. Triazoloquinazoline andpyrazolotriazolopyrimidine derivatives according to claim 5, which areselected from compound in which A is a pyrazole ring and R² is a phenylgroup having any one of lower alkoxy group, lower alkyl group or halogenatom as a substituent, compound in which A is a benzene ring and R² is aphenyl group having one group selected from lower alkoxy group, halogenatom and hydroxy group as a substituent, and compound in which A is abenzene ring substituted with one halogen atom and R² is a phenyl group.7. Triazoloquinazoline and pyrazolotriazolopyrimidine derivativesaccording to claim 6, which are selected from5-n-butyl-2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,5-n-butyl-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline,5-n-butyl-2-(4-ethoxyphenyl)-1,2,4-triazolo[1,5-c]quinazoline and5-n-butyl-9-chloro-2-phenyl-1,2,4-triazolo[1,5-c]quinazoline. 8.Triazoloquinazoline and pyrazolotriazolopyrimidine derivatives accordingto claim 5, wherein R² is a phenyl group which has a lower alkyl groupor a halogen atom at the 4-position.
 9. Triazoloquinazoline andpyrazolotriazolopyrimidine derivatives according to claim 8, which areselected from5-n-butyl-2-(4-chlorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,5-n-butyl-2-(4-fluorophenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,5-n-butyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,5-n-butyl-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-c]quinazoline,5-n-butyl-2-(4-bromophenyl)-1,2,4-triazolo[1,5-c]quinazoline and5-n-butyl-2-(4-chlorophenyl)-9-chloro-1,2,4-triazolo[1,5-c]quinazoline.10. Triazoloquinazoline and pyrazolotriazolopyrimidine derivativesaccording to claim 9, which are selected from5-n-butyl-2-(4-methylphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidineand 5-n-butyl-24-bromophenyl)-1,2,4-tiazolo[1,5-c]quinazoline.
 11. Apharmaceutical composition comprising a compound selected from thetriazoloquinazoline and pyrazolotriazolopyrimidine derivatives of anyone of claims 1 to 10, and a pharmaceutically acceptable carrier.
 12. Anadenosine A3 receptor affinitive agent comprising a compound selectedfrom the triazoloquinazoline and pyrazolotriazolopyrimidine derivativesof any one of claims 1 to 10 as an active ingredient.
 13. Anintraocular-pressure reducing agent comprising a compound selected fromthe triazoloquinazoline and pyrazolotriazolopyrimidine derivatives ofany one of claims 1 to 10 as an active ingredient.
 14. A pharmaceuticalpreparation for prevention or treatment of glaucoma, comprising acompound selected from the triazoloquinazoline andpyrazolotriazolopyrimidine derivatives of any one of claims 1 to 10 asan active ingredient.
 15. An intraocular-pressure reducing method, whichcomprises administering an effective amount of a compound selected fromthe triazoloquinazoline and pyrazolotriazolopyrimidine derivatives ofclaims 1 to 10 to a patient having an enhanced intraocular pressure. 16.Use of a compound selected from the triazoloquinazoline andpyrazolotriazolopyrimidine derivatives of claims 1 to 10 for reductionof an intraocular pressure of a patient having an enhanced intraocularpressure.
 17. Use of a compound selected from the triazoloquinazolineand pyrazolotriazolopyrimidine derivatives of claims 1 to 10 forproduction of a preventive or remedy for glaucoma.